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

• ClinicalTrials.gov Identifier: NCT04362813
• Recruitment Status: Completed
• First Posted: April 27, 2020
• Results First Posted: August 16, 2021
• Last Update Posted: January 24, 2022
• Sponsor: Novartis Pharmaceuticals
• Information provided by (Responsible Party): Novartis ( Novartis Pharmaceuticals )

Study Description

Brief Summary:

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).

Condition or disease	Intervention/treatment	Phase
Cytokine Release Syndrome (CRS) in Patients With COVID-19-induced Pneumonia	Drug: Canakinumab; Drug: Placebo	Phase 3

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 Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 454 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: 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)
• Actual Study Start Date: April 30, 2020
• Actual Primary Completion Date: September 16, 2020
• Actual Study Completion Date: December 22, 2020

Arms and Interventions

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 Name: 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.

Outcome Measures

Primary Outcome Measures :

1. Participants Who Survived Without Requiring Invasive Mechanical Ventilation From Day 3 to Day 29, Primary Analysis [ Time Frame: Day 3 to Day 29 ]
   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.

Secondary Outcome Measures :

1. COVID-19-related Death After Study Treatment [ Time Frame: 29 days ]
   Participants with COVID-19 related (as assessed by investigator) death up to Day 29
2. Geometric Mean Ratio to Baseline in the C-reactive Protein (CRP) [ Time Frame: 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. ]
   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.
3. Geometric Mean Ratio to Baseline in the D-dimer [ Time Frame: 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. ]

   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.

4. Geometric Mean Ratio to Baseline in Ferritin [ Time Frame: 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. ]
   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.
5. Number of Participants With Treatment Emergent Adverse Events [ Time Frame: Up to day 127 ]

   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).

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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

Contacts and Locations

Locations

United States, Alabama

Novartis Investigative Site

Birmingham, Alabama, United States, 35294

United States, California

Novartis Investigative Site

Glendale, California, United States, 91206

Novartis Investigative Site

San Francisco, California, United States, 94110

Novartis Investigative Site

San Francisco, California, United States, 94143

United States, Illinois

Novartis Investigative Site

Chicago, Illinois, United States, 60611

United States, Maryland

Novartis Investigative Site

Baltimore, Maryland, United States, 21201

United States, Massachusetts

Novartis Investigative Site

Boston, Massachusetts, United States, 02115

Novartis Investigative Site

Boston, Massachusetts, United States, 02118

United States, New York

Novartis Investigative Site

Brooklyn, New York, United States, 11219

United States, North Carolina

Novartis Investigative Site

Chapel Hill, North Carolina, United States, 27599

United States, Ohio

Novartis Investigative Site

Cleveland, Ohio, United States, 44106-5000

United States, Pennsylvania

Novartis Investigative Site

Philadelphia, Pennsylvania, United States, 19140

United States, Texas

Novartis Investigative Site

Houston, Texas, United States, 77030

United States, Virginia

Novartis Investigative Site

Richmond, Virginia, United States, 23298

United States, Washington

Novartis Investigative Site

Tacoma, Washington, United States, 98405

France

Novartis Investigative Site

Toulouse Cedex 4, France, 31054

Italy

Novartis Investigative Site

Bergamo, BG, Italy, 24127

Novartis Investigative Site

Cona, FE, Italy, 44100

Russian Federation

Novartis Investigative Site

Barnaul, Russian Federation, 656045

Novartis Investigative Site

Moscow, Russian Federation, 111539

Novartis Investigative Site

Moscow, Russian Federation, 121309

Novartis Investigative Site

Moscow, Russian Federation, 123056

Novartis Investigative Site

Moscow, Russian Federation, 123182

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

Spain

Novartis Investigative Site

Hospitalet de Llobregat, Barcelona, Spain, 08907

Novartis Investigative Site

Barcelona, Catalunya, Spain, 08035

Novartis Investigative Site

San Sebastian de los Reyes, Madrid, Spain, 28702

Novartis Investigative Site

Madrid, Spain, 28034

Novartis Investigative Site

Madrid, Spain, 28040

Novartis Investigative Site

Madrid, Spain, 28041

United Kingdom

Novartis Investigative Site

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

Sponsors and Collaborators

Novartis Pharmaceuticals

Investigators

• Study Director: Novartis Pharmaceuticals; Novartiis Pharmaceuticals

  Study Documents (Full-Text)

Documents provided by Novartis ( Novartis Pharmaceuticals ):

Study Protocol  [PDF] June 1, 2020

Statistical Analysis Plan  [PDF] February 15, 2021

More Information

Additional Information:

JAMA 20 July 2021 

A Plain Language Trial Summary is available on novctrd.com 

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

• Responsible Party: Novartis Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT04362813
• Other Study ID Numbers: CACZ885D2310; 2020-001370-30 ( EudraCT Number )
• First Posted: April 27, 2020
• Results First Posted: August 16, 2021
• Last Update Posted: January 24, 2022
• Last Verified: January 2022

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Undecided
• 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.

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Novartis ( Novartis Pharmaceuticals ):

COVID-19; cytokine release syndrome; SARS-CoV-2; canakinumab; COVID; coronavirus; CAN-COVID; pneumonia; CRS

Additional relevant MeSH terms:

COVID-19; Pneumonia; Syndrome; Cytokine Release Syndrome; Disease; Pathologic Processes; Pneumonia, Viral; Respiratory Tract Infections; Infections; Virus Diseases; Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Lung Diseases; Respiratory Tract Diseases; Systemic Inflammatory Response Syndrome; Inflammation; Shock