Study of Efficacy and Safety of Canakinumab Treatment for CRS in Participants With COVID-19-induced Pneumonia (CAN-COVID)

Phase 3 Multicenter, Randomized, Double-blind, Placebo-controlled Study to Assess the Efficacy and Safety of Canakinumab on Cytokine Release Syndrome in Patients With COVID-19-induced Pneumonia (CAN-COVID)

This was a multicenter, randomized, double-blind, placebo-controlled study to assess the efficacy and safety of canakinumab plus standard-of-care (SOC) compared with placebo plus SOC in patients with COVID-19-induced pneumonia and cytokine release syndrome (CRS).

Study Overview

• Status: Completed
• Conditions: Cytokine Release Syndrome (CRS) in Patients With COVID-19-induced Pneumonia
• Intervention / Treatment: Drug: Canakinumab; Drug: Placebo

Detailed Description

This was a Phase III, multicenter, randomized, double-blind, placebo-controlled study to assess the efficacy and safety of canakinumab in patients with COVID-19-induced pneumonia and cytokine release syndrome (CRS). The study enrolled patients to canakinumab or placebo, in addition to standard of care (SOC) per local practice, which may have included anti-viral treatment, corticosteroids and/or supportive care.

Patients who met the inclusion/exclusion criteria were randomized in a 1:1 ratio to either canakinumab + SOC or placebo + SOC and were dosed immediately after ensuring that the patient met all eligibility criteria. Patients in the canakinumab arm were dosed on Day 1 with canakinumab 450 mg for body weight of 40-<60 kg, 600 mg for 60-80 kg or 750 mg for >80 kg in 250 mL of 5% dextrose infused IV over 2 hours. Patients in the placebo arm were administered with 250 mL of 5% dextrose infused IV over 2 hours.

The study included:

• Screening period of 0-1 day
• Study period from initial dose on Day 1 to Day 29 or hospital discharge
• Follow-up to Day 127 The primary objective was to demonstrate the benefit of canakinumab + SOC in increasing the chance of survival without ever requiring invasive mechanical ventilation among patients with COVID-19-induced pneumonia and CRS.

• Study Type: Interventional
• Enrollment (Actual): 454
• Phase: Phase 3

Contacts and Locations

Study Locations

• France
  • Toulouse Cedex 4, France, 31054
    • Novartis Investigative Site
• Italy
  • BG
    • Bergamo, BG, Italy, 24127
      • Novartis Investigative Site
  • FE
    • Cona, FE, Italy, 44100
      • Novartis Investigative Site
• Russian Federation
  • Barnaul, Russian Federation, 656045
    • Novartis Investigative Site
  • Moscow, Russian Federation, 121309
    • Novartis Investigative Site
  • Moscow, Russian Federation, 123182
    • Novartis Investigative Site
  • Moscow, Russian Federation, 123056
    • Novartis Investigative Site
  • Moscow, Russian Federation, 111539
    • Novartis Investigative Site
  • Ryazan, Russian Federation, 390039
    • Novartis Investigative Site
  • S-Petersburg, Russian Federation, 194354
    • Novartis Investigative Site
  • Saint Petersburg, Russian Federation, 197022
    • Novartis Investigative Site
  • Sestroretsk, Russian Federation, 197706
    • Novartis Investigative Site
  • St Petersburg, Russian Federation, 193312
    • Novartis Investigative Site
• Spain
  • Madrid, Spain, 28041
    • Novartis Investigative Site
  • Madrid, Spain, 28034
    • Novartis Investigative Site
  • Madrid, Spain, 28040
    • Novartis Investigative Site
  • Barcelona
    • Hospitalet de Llobregat, Barcelona, Spain, 08907
      • Novartis Investigative Site
  • Catalunya
    • Barcelona, Catalunya, Spain, 08035
      • Novartis Investigative Site
  • Madrid
    • San Sebastian de los Reyes, Madrid, Spain, 28702
      • Novartis Investigative Site
• United Kingdom
  • Barnet, United Kingdom, EN5 3DJ
    • Novartis Investigative Site
  • Coventry, United Kingdom, CV2 2DX
    • Novartis Investigative Site
  • Leeds, United Kingdom, LS9 7TF
    • Novartis Investigative Site
  • London, United Kingdom, NW3 2QG
    • Novartis Investigative Site
  • London, United Kingdom, SE5 9RS
    • Novartis Investigative Site
• United States
  • Alabama
    • Birmingham, Alabama, United States, 35294
      • Novartis Investigative Site
  • California
    • Glendale, California, United States, 91206
      • Novartis Investigative Site
    • San Francisco, California, United States, 94143
      • Novartis Investigative Site
    • San Francisco, California, United States, 94110
      • Novartis Investigative Site
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Novartis Investigative Site
  • Maryland
    • Baltimore, Maryland, United States, 21201
      • Novartis Investigative Site
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Novartis Investigative Site
    • Boston, Massachusetts, United States, 02118
      • Novartis Investigative Site
  • New York
    • Brooklyn, New York, United States, 11219
      • Novartis Investigative Site
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27599
      • Novartis Investigative Site
  • Ohio
    • Cleveland, Ohio, United States, 44106-5000
      • Novartis Investigative Site
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19140
      • Novartis Investigative Site
  • Texas
    • Houston, Texas, United States, 77030
      • Novartis Investigative Site
  • Virginia
    • Richmond, Virginia, United States, 23298
      • Novartis Investigative Site
  • Washington
    • Tacoma, Washington, United States, 98405
      • Novartis Investigative Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Key inclusion Criteria:

• Adults ≥ 18 years old (for US only: patients ≥ 12 years old, although no children ever enrolled. This was an adult trial.)
• Body weight ≥40 kg
• Informed consent must be obtained prior to participation in this study. For US patients 12 - < 18 years old; parent/guardian consent must be obtained and assent if applicable.
• Clinically diagnosed with SARS-CoV-2 virus by PCR or by other approved diagnostic methodology
• Hospitalized with COVID-19-induced pneumonia evidenced by chest x-ray or CT scan with pulmonary infiltrates
• SpO2 ≤ 93% on room air or arterial oxygen partial pressure (PaO2)/ fraction of inspired oxygen (FiO2) < 300mmHg
• C-reactive protein ≥20 mg/L or ferritin level ≥600 µg/L

Key exclusion Criteria:

• History of hypersensitivity to canakinumab or to biologic drugs
• Intubated and on mechanical ventilation (invasive) at time of randomization
• Treatment with immunomodulators or immunosuppressant drugs, including but not limited to tocilizumab, TNF inhibitors and anti-IL-17 agents within 5 half-lives or 30 days (whichever is longer) prior to randomization with the exception of anakinra which is excluded within 5 half-lives only. Note: Immunomodulators (topical or inhaled) for asthma and atopic dermatitis and corticosteroids (any route of administration) are permitted.
• Suspected or known untreated active bacterial, fungal, viral, or parasitic infection with the exception of COVID-19

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: DOUBLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Canakinumab; Canakinumab 450 mg for body weight 40-<60 kg, 600 mg for 60-80 kg or 750 mg for >80 kg in 250 mL of 5% dextrose infused IV over 2 hours. Single dose on Day 1.	Drug: Canakinumab; Canakinumab 450 mg for body weight 40-<60 kg, 600 mg for 60-80 kg or 750 mg for >80 kg in 250 mL of 5% dextrose infused IV over 2 hours. Single dose on Day 1.; Other Names: ACZ885
PLACEBO_COMPARATOR: Placebo; 250 mL of 5% dextrose infused IV over 2 hours. Single dose on Day 1.	Drug: Placebo; 250 mL of 5% dextrose infused IV over 2 hours. Single dose on Day 1.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Participants Who Survived Without Requiring Invasive Mechanical Ventilation From Day 3 to Day 29, Primary Analysis	Number of responders who survived without requiring invasive mechanical ventilation from Day 3 to Day 29. An early dropout without requiring invasive mechanical ventilation is considered as a responder if discharged from hospital with 9-point ordinal scale<=1 or with last 9-point ordinal scale on/after Day 15 better than baseline.	Day 3 to Day 29

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
COVID-19-related Death After Study Treatment	Participants with COVID-19 related (as assessed by investigator) death up to Day 29	29 days
Geometric Mean Ratio to Baseline in the C-reactive Protein (CRP)	Measurement of C Reactive Protein (mg/L), Serum Or Plasma over time. The level of C-reactive protein (CRP), which can be measured in the blood, increases when there's inflammation in the body. Lower values of ratio to baseline in the CRP indicates less inflammation. The ratio to baseline at each time point (day) for each patient is calculated as the level of a specific biomarker at the time point divided by the baseline level of the biomarker, where baseline is the last non-missing value before study treatment. The geometric mean of ratio to baseline at each time point for each treatment group is calculated by first averaging the logarithms of the ratios to baseline and then take the exponential function of the same base.	Over time and up to day 29: Baseline, Day 2, Day 3, Day 5, Day 7, Day 9, Day 11, Day 13, Day 15, Day 17, Day 19, Day 21, Day 23, Day 25, Day 27 and Day 29.
Geometric Mean Ratio to Baseline in the D-dimer	Clinical chemistry measurement D-Dimer (mg/L FEU), Blood in a blood sample over time D-dimer is one of the protein fragments produced when a blood clot gets dissolved in the body. The ratio to baseline at each time point (day) for each patient is calculated as the level of a specific biomarker at the time point divided by the baseline level of the biomarker, where baseline is the last non-missing value before study treatment. The geometric mean of ratio to baseline at each time point for each treatment group is calculated by first averaging the logarithms of the ratios to baseline and then take the exponential function of the same base.	Over time and up to day 29: Baseline, Day 2, Day 3, Day 5, Day 7, Day 9, Day 11, Day 13, Day 15, Day 17, Day 19, Day 21, Day 23, Day 25, Day 27 and Day 29.
Geometric Mean Ratio to Baseline in Ferritin	Clinical chemistry measurement for amount of ferritin (ug/L) in Serum. The ratio to baseline at each time point (day) for each patient is calculated as the level of a specific biomarker at the time point divided by the baseline level of the biomarker, where baseline is the last non-missing value before study treatment. The geometric mean of ratio to baseline at each time point for each treatment group is calculated by first averaging the logarithms of the ratios to baseline and then take the exponential function of the same base.	Over time and up to day 29: Baseline, Day 2, Day 3, Day 5, Day 7, Day 9, Day 11, Day 13, Day 15, Day 17, Day 19, Day 21, Day 23, Day 25, Day 27 and Day 29.
Number of Participants With Treatment Emergent Adverse Events	Number of participants with treatment emergent adverse events, including changes from baseline in vital signs and laboratory results qualifying and reported as adverse events. Safety was monitored from the canakinumab or placebo dose (Day 1) up to 126 days post-dose (Day 127).	Up to day 127

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals
• Investigators: Study Director: Novartis Pharmaceuticals, Novartiis Pharmaceuticals

Publications and helpful links

General Publications

• Sedhai YR, Sears M, Vecchie A, Bonaventura A, Greer J, Spence K, Tackett H, Turner J, Pak M, Patel N, Black M, Wohlford G, Clary RE, Duke C, Hardin M, Kemp H, Priday A, Sims EK Jr, Mihalick V, Ho AC, Ibe I, Harmon M, Markley R, Van Tassell B, Abbate A. Clinical trial enrollment at a rural satellite hospital during COVID-19 pandemic. J Clin Transl Sci. 2021 Apr 8;5(1):e136. doi: 10.1017/cts.2021.777. eCollection 2021.
• Caricchio R, Abbate A, Gordeev I, Meng J, Hsue PY, Neogi T, Arduino R, Fomina D, Bogdanov R, Stepanenko T, Ruiz-Seco P, Gonzalez-Garcia A, Chen Y, Li Y, Whelan S, Noviello S; CAN-COVID Investigators. Effect of Canakinumab vs Placebo on Survival Without Invasive Mechanical Ventilation in Patients Hospitalized With Severe COVID-19: A Randomized Clinical Trial. JAMA. 2021 Jul 20;326(3):230-239. doi: 10.1001/jama.2021.9508.

Helpful Links

• JAMA 20 July 2021
• A Plain Language Trial Summary is available on novctrd.com

Study record dates

Study Major Dates

• Study Start (ACTUAL): April 30, 2020
• Primary Completion (ACTUAL): September 16, 2020
• Study Completion (ACTUAL): December 22, 2020

Study Registration Dates

• First Submitted: April 24, 2020
• First Submitted That Met QC Criteria: April 24, 2020
• First Posted (ACTUAL): April 27, 2020

Study Record Updates

• Last Update Posted (ACTUAL): January 24, 2022
• Last Update Submitted That Met QC Criteria: January 21, 2022
• Last Verified: January 1, 2022

More Information

Terms related to this study

• Keywords: SARS-CoV-2; COVID-19; COVID; pneumonia; coronavirus; cytokine release syndrome; CRS; canakinumab; CAN-COVID
• Additional Relevant MeSH Terms: Pathologic Processes; Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Virus Diseases; Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Pneumonia, Viral; Lung Diseases; Systemic Inflammatory Response Syndrome; Inflammation; Disease; Shock; COVID-19; Syndrome; Pneumonia; Cytokine Release Syndrome
• Other Study ID Numbers: CACZ885D2310; 2020-001370-30 (EUDRACT_NUMBER)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED
• IPD Plan Description: Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations. This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No