Efficacy of Early Administration of Tocilizumab in COVID-19 Patients

• ClinicalTrials.gov Identifier: NCT04346355
• Recruitment Status: Terminated
• First Posted: April 15, 2020
• Last Update Posted: June 22, 2020
• Sponsor: Azienda Unità Sanitaria Locale Reggio Emilia
• Information provided by (Responsible Party): Azienda Unità Sanitaria Locale Reggio Emilia

Tracking Information

• First Submitted Date: April 12, 2020
• First Posted Date: April 15, 2020
• Last Update Posted Date: June 22, 2020
• Actual Study Start Date: March 31, 2020
• Actual Primary Completion Date: June 6, 2020 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: April 14, 2020)

Entry into Intensive Care with invasive mechanical ventilation or death from any cause or clinical aggravation [ Time Frame: two weeks from participants' allocation to study arm ]

Entry into Intensive Care with invasive mechanical ventilation or death from any cause or clinical aggravation documented by the finding of a PaO2 / FiO2 ratio <150mm / Hg confirmed by a second arterial blood gas (ABG) measurement within four hours

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: April 14, 2020)

• Death from any cause [ Time Frame: Two weeks from participants' allocation to study arm ]
  Death
• Tocilizumab toxicity [ Time Frame: Two weeks from participants' allocation to study arm ]
  Adverse events (AE) classified according to the NCI Common Terminology Criteria for Adverse Events (CTCAE) scale
• Levels of interleukin-6 and C-reactive protein (CRP) and their correlation with the effectiveness of the treatment [ Time Frame: Two weeks from participants' allocation to study arm ]
  Levels of ferritin, lactate dehydrogenase and D-dimer and their correlation with the effectiveness of the treatment
• Evaluate the progress of the PaO2 / FiO2 ratio [ Time Frame: Two weeks from participants' allocation to study arm ]
  Changes from baseline of the PaO2 / FiO2 ratio
• Evaluate the trend over time of the lymphocyte count [ Time Frame: Two weeks from participants' allocation to study arm ]
  Changes from baseline of the lymphocyte count

• Original Secondary Outcome Measures: Same as current
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Efficacy of Early Administration of Tocilizumab in COVID-19 Patients
• Official Title: An Open-label Randomized Multicenter Study to Evaluate the Efficacy of Early Administration of Tocilizumab (TCZ) in Patients With COVID-19 Pneumonia
• Brief Summary: The clinical study aims at assessing whether early administration of Tocilizumab compared to late administration of Tocilizumab can reduce the number of patients with COVID-19 pneumonia who require mechanical ventilation. The clinical study includes patients with recent-onset COVID-19 pneumonia who require hospital care, but not invasive or semi-invasive mechanical ventilation procedures.
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: COVID-19 Pneumonia

Intervention

Drug: Tocilizumab

In case of aggravation of COVID-19 pneumonia, according to protocol criteria, participants will receive 8 mg/kg IV up to a maximum of 800 mg with repetition of the same dosage after 12 hours

Other Name: Standard of care

Study Arms

• Experimental: Experimental Arm
  Tocilizumab within 8 hours from entering the study + standard of care; 8 mg/kg IV up to a maximum of 800 mg with repetition of the same dosage after 12 hours
  Intervention: Drug: Tocilizumab
• Control Arm
  Standard of care; In the event of aggravation of COVID-19 pneumonia, according to protocol criteria, participants will receive 8 mg/kg IV up to a maximum of 800 mg with repetition of the same dosage after 12 hours
  Intervention: Drug: Tocilizumab

• Publications *: Salvarani C, Dolci G, Massari M, Merlo DF, Cavuto S, Savoldi L, Bruzzi P, Boni F, Braglia L, Turra C, Ballerini PF, Sciascia R, Zammarchi L, Para O, Scotton PG, Inojosa WO, Ravagnani V, Salerno ND, Sainaghi PP, Brignone A, Codeluppi M, Teopompi E, Milesi M, Bertomoro P, Claudio N, Salio M, Falcone M, Cenderello G, Donghi L, Del Bono V, Colombelli PL, Angheben A, Passaro A, Secondo G, Pascale R, Piazza I, Facciolongo N, Costantini M; RCT-TCZ-COVID-19 Study Group. Effect of Tocilizumab vs Standard Care on Clinical Worsening in Patients Hospitalized With COVID-19 Pneumonia: A Randomized Clinical Trial. JAMA Intern Med. 2021 Jan 1;181(1):24-31. doi: 10.1001/jamainternmed.2020.6615.

Recruitment Information

• Recruitment Status: Terminated
• Actual Enrollment (submitted: June 18, 2020): 126
• Original Estimated Enrollment (submitted: April 14, 2020): 398
• Actual Study Completion Date: June 6, 2020
• Actual Primary Completion Date: June 6, 2020 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• age > 18 years
• Informed consent for participation in the study
• Real time polymerase chain reaction (PCR) diagnosis of Sars-CoV2 infection
• Hospitalization due to clinical / instrumental diagnosis (high resolution chest CT scan or chest x-ray or pulmonary ultrasound)
• Presence of acute respiratory distress syndrome with arterial partial pressure of oxygen / fraction of inspired oxygen (PaO2 / FiO2) between 200 and 300 mm/Hg
• Presence of exaggerated inflammatory response defined by the presence of at least 1 of the following criteria:
• At least one body temperature measurement >38° C in the past two days;
• Serum CRP greater than or equal to 10 mg/dl;
• CRP increase of at least twice the basal value

Exclusion Criteria:

• Patients with respiratory distress syndrome with arterial partial pressure of oxygen / fraction of inspired oxygen (PaO2 / FiO2) <200 mm/Hg or
• Patients in non-invasive ventilation or
• Patients in invasive ventilation or presence of shock or presence of concomitant organ failure that requires admission to the Intensive Care Unit
• Severe heart and kidney failure
• Pregnant or breastfeeding patient
• Patient who, in the opinion of the clinician or by the patient's express will, will not go to intensive care regardless of the evolution of the lung picture.
• Known hypersensitivity to TCZ or its excipients
• Patient being treated with immuno-depressors or anti-rejection drugs
• Known active infections or other clinical conditions that contraindicate TCZ and cannot be treated or resolved according to the physician's judgment
• glutamate-pyruvate transaminase (GPT) or glutamine oxaloacetic transaminase (GOT) > 5 times the upper limit of the norm
• Neutrophils <500 /mmc
• Platelets <50.000 /mmc
• Diverticulitis or intestinal perforation
• Suspicion of latent tuberculosis

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Italy

Administrative Information

• NCT Number: NCT04346355
• Other Study ID Numbers: RCT-TCZ-COVID-19; 2020-001386-37 ( EudraCT Number )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• 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

• IPD Sharing Statement: Not Provided
• Current Responsible Party: Azienda Unità Sanitaria Locale Reggio Emilia
• Original Responsible Party: Same as current
• Current Study Sponsor: Azienda Unità Sanitaria Locale Reggio Emilia
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: Carlo Salvarani, M.D.; Azienda Unità Sanitaria Locale-IRCCS di Reggio Emilia
• Study Director: Massimo Costantini, Ph.D.; Azienda Unità Sanitaria Locale-IRCCS di Reggio Emilia

• PRS Account: Azienda Unità Sanitaria Locale Reggio Emilia
• Verification Date: June 2020