Serum IL-6 and Soluble IL-6 Receptor in Severe COVID-19 Pneumonia Treated With Tocilizumab (UHID-COVID19)

Prognostic Value of Serum Interleukin-6 (IL-6) and Soluble Interleukin-6 Receptor (sIL-6R) in Severe Coronavirus Disease (COVID-19) Pneumonia Treated With Tocilizumab - a Prospective Single Center Study (UHID-COVID19)

This is a single arm, prospective, observational, single center study to assess the role of interleukin-6 (IL-6) and soluble interleukin 6 receptor (sIL-6R) as predictors of efficacy and safety outcomes in patients with severe coronavirus disease (COVID-19) pneumonia treated with tocilizumab. At least 30 patients will be enrolled who are diagnosed with severe COVID-19 pneumonia and meet the entry criteria.

Study Overview

• Status: Unknown
• Conditions: COVID-19; Severe Pneumonia
• Intervention / Treatment: Drug: Tocilizumab 20 MG/ML Intravenous Solution [ACTEMRA]

Detailed Description

Patients must be at least 18 years of age with severe COVID-19 pneumonia (and/or ARDS) confirmed per World Health Organization (WHO) criteria, and evidence of pulmonary infiltration (by chest X-ray and/or CT scan), including a virological confirmation of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection by positive polymerase chain reaction (PCR) of any specimen; e.g., respiratory, blood, urine, stool, other bodily fluid.

At the time of enrollment, patients have to fulfill criteria of the local recommendations for the treatment with tocilizumab (TCZ): hypoxemia (defined as arterial oxygen partial pressure/fraction of inspired oxygen (PaO2/FiO2) ratio ≤300 mmHg and/or peripheral capillary oxygen saturation (SpO2) ≤93%) regardless of the oxygenation method including low-flow oxygen administration on nasal cannula or mask with oxygen flow rate of > 12 liters per minute, high-flow oxygen through nasal cannula, noninvasive ventilation (NIV) whatever the modalities of ventilation, invasive ventilation through tracheal intubation or tracheostomy, and extracorporeal oxygenation, despite being on standard of care (SOC), which may include anti-viral treatment, low dose steroids, antimalarials and supportive treatment and care.

Patients in whom, in the opinion of the treating physician, progression to death is imminent and inevitable within the next 24 hours, will be excluded from the study. Patients with active tuberculosis (TB) or suspected active bacterial, fungal, viral, or other infection (besides COVID-19) will be excluded from the study.

Patients will receive one infusion of TCZ 8 mg/kg i.v., with a maximum dose of 800 mg, and SOC treatment according to local guidelines (hydroxychloroquine or/and lopinavir/ritonavir or/and remdesivir).

If the clinical signs or symptoms worsen or do not improve (reflected by sustained fever or at least a one-category worsening on the 7-category ordinal scale of clinical status), one additional infusion of blinded treatment of TCZ or placebo may be given, after more than 12 hours per local protocol.

The study assessments to be conducted include the following: physical examination, vital signs, oxygen saturation, assessment of consciousness, presence and absence of respiratory support, adverse events, concomitant therapies, clinical laboratory tests, and nasopharyngeal swabs.

• Study Type: Observational
• Enrollment (Anticipated): 30

Contacts and Locations

Study Locations

• Croatia
  • Zagreb, Croatia, 10000
    • Recruiting
    • University Hospital for Infectious Diseases "Dr Fran Mihaljević"
    • Contact: Rok Civljak, MD, PhD; Phone Number: ++385914012547; Email: rcivljak@bfm.hr
    • Contact: Arijana Pavelic, BA; Phone Number: ++385914012584; Email: apavelic@bfm.hr
    • Principal Investigator: Rok Civljak, MD, PhD
    • Principal Investigator: Miroslav Mayer, MD, PhD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Probability Sample

Study Population

Patients ≥18 yrs with severe COVID-19 pneumonia (and/or ARDS) confirmed per WHO criteria, and evidence of pulmonary infiltration (by chest X-ray and/or CT scan), including a virological confirmation of SARS-CoV-2 infection by PCR of any specimen; e.g., respiratory, blood, urine, stool, other bodily fluid. At enrollment, patients have to fulfill criteria of local recommendations for tocilizumab treatment: hypoxemia regardless of the oxygenation method including low-flow oxygen administration on nasal cannula or mask with oxygen flow rate of > 12 liters per minute, high-flow oxygen through nasal cannula, noninvasive ventilation whatever the modalities of ventilation, invasive ventilation through tracheal intubation or tracheostomy, and extracorporeal oxygenation, despite being on SOC, which may include anti-viral treatment, low dose steroids, antimalarials and supportive treatment and care.

Description

Inclusion Criteria:

• Signed Informed Consent Form by any patient capable of giving consent, or, when the patient is not capable of giving consent, by his or her legal/authorized representative
• Age ≥18years at time of signing Informed Consent Form
• Ability to comply with the study protocol, in the investigator's judgment
• Hospitalized due to severe COVID-19 pneumonia (and/or ARDS) confirmed per World Health Organization criteria, and evidence of pulmonary infiltration (by chest X-ray and/or CT scan), including a virological confirmation of SARS-CoV-2 infection by positive PCR of any specimen; e.g., respiratory, blood, urine, stool, other bodily fluid
• Hypoxemia (defined as a PaO2/FiO2 ratio ≤300 mmHg and/or SpO2≤93%) regardless of their oxygenation device (including low-flow oxygen administration on nasal cannula or mask with oxygen flow rate of > 12 liters per minute), high-flow oxygen through nasal cannula, noninvasive ventilation (NIV) whatever the modalities of ventilation, invasive ventilation through tracheal intubation or tracheostomy, and extracorporeal oxygenation, despite being on SOC, which may include anti-viral treatment, low dose steroids, and supportive care

Exclusion Criteria:

• Known severe allergic reactions to TCZ or other monoclonal antibodies
• Active TB infection
• Suspected active bacterial, fungal, viral, or other infection (besides COVID-19)
• In the opinion of the investigator, progression to death is imminent and inevitable within the next 24 hours, irrespective of the provision of treatments
• Have received oral anti-rejection or immunomodulatory drugs (including TCZ) within the past 6 months
• alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >10 times the upper limit of the normality detected within 24 hours at screening or at baseline
• absolute neutrophil count (ANC) <1000/µL at screening and baseline
• Platelet count <50,000/µL at screening and baseline
• Pregnant or breastfeeding, or positive pregnancy test in a pre-dose examination
• Any serious medical condition or abnormality of clinical laboratory tests that, in the investigator's judgment, precludes the patient's safe participation in the study

Study Plan

How is the study designed?

Design Details

• Observational Models: Case-Only
• Time Perspectives: Prospective

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
tocilizumab; one infusion of TCZ 8 mg/kg i.v., with a maximum dose of 800 mg, and SOC treatment according to local guidelines (hydroxychloroquine or/and lopinavir/ritonavir or/and remdesivir).	Drug: Tocilizumab 20 MG/ML Intravenous Solution [ACTEMRA]; 1 - 8 mg per kg of body weight once, maximal 800 mg per dose (can be repeated once more after 12 hours, per clinician's assessment); Other Names: RoActemra, Anatomical Therapeutic Chemical (ATC) Code L04AC07

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
serum interleukin-6 and soluble interleukin-6 receptor as biomarkers of clinical outcomes in patients with severe coronavirus disease (COVID-19) pneumonia treated with tocilizumab	to evaluate the role of laboratory markers as predictors of survival in severe COVID-19 pneumonia patients treated with tocilizumab	baseline
serum interleukin-6 and soluble interleukin-6 receptor as biomarkers of clinical outcomes in patients with severe coronavirus disease (COVID-19) pneumonia treated with tocilizumab	to evaluate the role of laboratory markers as predictors of survival in severe COVID-19 pneumonia patients treated with tocilizumab	24 hours post treatment
serum interleukin-6 and soluble interleukin-6 receptor as biomarkers of clinical outcomes in patients with severe coronavirus disease (COVID-19) pneumonia treated with tocilizumab	to evaluate the role of laboratory markers as predictors of survival in severe COVID-19 pneumonia patients treated with tocilizumab	48 hours post treatment
serum interleukin-6 and soluble interleukin-6 receptor as biomarkers of clinical outcomes in patients with severe coronavirus disease (COVID-19) pneumonia treated with tocilizumab	to evaluate the role of laboratory markers as predictors of survival in severe COVID-19 pneumonia patients treated with tocilizumab	on Day 7
serum interleukin-6 and soluble interleukin-6 receptor as biomarkers of clinical outcomes in patients with severe coronavirus disease (COVID-19) pneumonia treated with tocilizumab	to evaluate the role of laboratory markers as predictors of survival in severe COVID-19 pneumonia patients treated with tocilizumab	on Day 28

Collaborators and Investigators

• Sponsor: University Hospital for Infectious Diseases, Croatia
• Investigators: Principal Investigator: Rok Civljak, MD, PhD, University Hospital for Infectious Diseases "Dr Fran Mihaljević"

Study record dates

Study Major Dates

• Study Start (Actual): June 16, 2020
• Primary Completion (Anticipated): April 16, 2021
• Study Completion (Anticipated): May 15, 2021

Study Registration Dates

• First Submitted: April 16, 2020
• First Submitted That Met QC Criteria: April 21, 2020
• First Posted (Actual): April 24, 2020

Study Record Updates

• Last Update Posted (Actual): November 12, 2020
• Last Update Submitted That Met QC Criteria: November 10, 2020
• Last Verified: June 1, 2020

More Information

Terms related to this study

• Keywords: COVID-19; tocilizumab; Interleukin-6; severe pneumonia
• Additional Relevant MeSH Terms: Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Virus Diseases; Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Pneumonia, Viral; Lung Diseases; COVID-19; Pneumonia
• Other Study ID Numbers: UHID-04

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Undecided

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No