Tocilizumab in COVID-19 Pneumonia (TOCIVID-19) (TOCIVID-19)

Multicenter Study on the Efficacy and Tolerability of Tocilizumab in the Treatment of Patients With COVID-19 Pneumonia

This study project includes a single-arm phase 2 study and a parallel cohort study, enrolling patients with COVID-19 pneumonia.

Study Overview

• Status: Active, not recruiting
• Conditions: COVID-19 Pneumonia
• Intervention / Treatment: Drug: Tocilizumab Injection

Detailed Description

Phase 2 study: this is a multicenter, single-arm, open-label, phase 2 study. All the patients enrolled are treated with tocilizumab. Two-week (14 days) and one-month (30 days) lethality rates are the co-primary endpoints.

The parallel cohort includes patients who are treated with tocilizumab and cannot enter the phase 2 study because:

1. emergency conditions or infrastructural or operational limits prevented registration before the administration of the experimental drug or
2. they had been intubated more than 24 hours before registration or
3. the phase 2 study has been closed due to reached sample size.

This means that, after closure of the phase 2 enrolment, patients who might be eligible for the phase 2 study will be included in the observational cohort study.

The same information planned for the phase 2 cohort is required also for the parallel cohort study whose sample size is not defined a priori, and that will close at the end of the overall project. All the patients enrolled are treated with tocilizumab.

In both study groups (phase 2 and parallel cohort), participants receive one dose of Tocilizumab 8 mg/kg (up to a maximum of 800mg per dose). A second administration (same dose) can be given after 12 hours if respiratory function has not recovered, at discretion of the Investigator.

• Study Type: Interventional
• Enrollment (Actual): 402
• Phase: Phase 2

Contacts and Locations

Study Locations

• Italy
  • Alessandria, Italy
    • Azienda Ospedaliera "SS. Antonio e Biagio e C. Arrigo" (Dipartimento Internistico SSD Reumatologia)
  • Busto Arsizio, Italy
    • Ospedale di Busto Arsizio ASST Valle Olona (U.O.C. Malattie Infettive)
  • Catania, Italy
    • A.O.U. Policlinico V. Emanuele (U.O. di Malattie infettive, U.O. di Anestesia e Rianimazione, U.O. di Medicina d'Urgenza)
  • Catania, Italy
    • AOE Cannizzaro di Catania (U.O. di Malattie Infettive, U.O. di Anestesia e Rianimazione, U.O.
  • Cosenza, Italy
    • Ospedale Annunziata Azienda Ospedaliera di Cosenza (U.O.C. Malattie Infettive)
  • Magenta, Italy
    • ASST OVEST MILANESE presidi Legnano - Magenta
  • Modena, Italy, 42100
    • Azienda Ospedaliero-Universitaria di Modena
  • Modena, Italy
    • A.O.U. di Modena (Dipartimento Chirurgie Generali e Specialità Chirurgiche - Struttura Complessa di Anestesia e Rianimazione I)
  • Modena, Italy
    • A.O.U. di Modena (Dipartimento Chirurgie Generali e Specialità Chirurgiche - Struttura Complessa di Anestesia e Rianimazione II)
  • Modena, Italy
    • A.O.U. di Modena (Dipartimento Medicine Specialistiche - Struttura Complessa Malattie Infettive)
  • Modena, Italy
    • Dipartimento Medicine Specialistiche - Struttura Complessa Malattie dell'Apparato Respiratorio
  • Naples, Italy, 80131
    • A.O.R.N. Ospedale dei Colli Monaldi-Cotugno-CTO (U.O.C. Oncologia)
  • Naples, Italy, 80131
    • National Cancer Institute
  • Naples, Italy
    • A.O.R.N. Ospedale dei Colli Monaldi-Cotugno-CTO (U.O.C. Anestesia Rianimazione e terapia intensiva)
  • Naples, Italy
    • A.O.R.N. Ospedale dei Colli Monaldi-Cotugno-CTO (U.O.C. Malattie Infettive ad indirizzo respiratorio)
  • Pesaro, Italy
    • A.O. Ospedali Riuniti Marche Nord - Presidio Ospedaliero San Salvatore di Pesaro (UOC Pronto Soccorso e Medicina d'Urgenza)
  • Pozzuoli, Italy
    • Denominazione: UOC di Medicina e Chirurgia d'Accettazione e d'Urgenza dell'Ospedale Santa Maria delle Grazie di Pozzuoli
  • Ravenna, Italy
    • Ospedale Santa Maria delle Croci, AUSL della Romagna (U.O. Anestesia e Rianimazione)
  • Reggio Calabria, Italy
    • Grande Ospedale Metropolitano, Reggio Calabria
  • Rimini, Italy
    • Ospedale Infermi, AUSL della Romagna (U.O. Malattie Infettive)
  • Rome, Italy
    • Policlinico Gemelli (U.O.C. Dipartimento Scienze di Laboratorio e Infettivologiche)
  • Varese, Italy
    • ASST Sette Laghi (Dipartimento di Medicina Interna)
  • Varese, Italy
    • ASST Sette Laghi (Dipartimento Emergenze ed Urgenze)
  • Varese, Italy
    • ASST Sette Laghi (U.O.C. Anestesia e Rianimazione Neurochirurgica e Generale)
  • Varese, Italy
    • ASST Sette Laghi (U.O.C. Malattie Infettive e Tropicali)
  • Verona, Italy
    • A.O.U. Integrata di Verona (Dip. Malattie Infettive)
  • Villafranca Di Verona, Italy
    • Ospedale Magalini (U.O. Malattie Infettive)

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Any gender
2. No age limit
3. Informed consent for participation in the study (consent can be oral if a written consent cannot be expressed. If the subject is incapable of giving an informed consent and an authorized representative is not available without a delay that would, in the opinion of the Investigator, compromise the potential life-saving effect of the treatment this can be administered without consent. Consent to remain in the research should be sought as soon the conditions of the patient will allow it)
4. Virological diagnosis of SARS-CoV-2 infection (real-time PCR)
5. Hospitalized due to clinical/instrumental diagnosis of pneumonia
6. Oxygen saturation at rest in ambient air ≤93% or requiring oxygen therapy or mechanical ventilation either non invasive or invasive (intubated)
7. Patients with criteria #4 and #5 who have been already treated with tocilizumab before registration are eligible for the observational retrospective cohort

Exclusion Criteria:

1. Known hypersensitivity to tocilizumab or its excipients
2. Known active infections or other clinical condition that contraindicate tocilizumab and cannot be treated or solved according to the judgement of the clinician
3. ALT / AST> 5 times the upper limit of the normality
4. Neutrophils <500 / mmc
5. Platelets <50.000 / mmc
6. Bowel diverticulitis or perforation

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: tocilizumab treatment; All the patients enrolled are treated with tocilizumab.	Drug: Tocilizumab Injection; Tocilizumab 8 mg/kg (up to a maximum of 800mg per dose). A second administration (same dose) can be given after 12 hours if respiratory function has not recovered, at discretion of the Investigator.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Lethality rate two weeks after registration	2-week lethality is defined as the ratio of the number of subjects dead within 14 days from study start out of phase 2 patients with baseline information.	up to 15 days
Lethality rate one month after registration	1-month lethality is defined as the ratio of the number of subjects dead within 30 days from study start out of phase 2 patients with baseline information.	up to 1 month

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Interleukin-6 level	IL-6 levels will be assessed using commercial ELISA method.	baseline, during treatment (cycle 1 and 2 every 12 hours) up to 1 month
Lymphocyte count	Lymphocyte count assessed by routinely used determination of blood count	baseline, during treatment (cycle 1 and 2 every 12 hours) up to 1 month
CRP (C-reactive protein) level	CRP is assessed by routinely used determination of CRP	baseline, during treatment (cycle 1 and 2 every 12 hours) up to 1 month
PaO2 (partial pressure of oxygen) / FiO2 (fraction of inspired oxygen, FiO2) ratio (or P/F ratio)	calculated from arterial blood gas analyses (values from 300 to 100)	baseline, during treatment (cycle 1 and 2 every 12 hours) up to 1 month
Change of the SOFA (Sequential Organ Failure Assessment)	It evaluates 6 variables, each representing an organ system (one for the respiratory, cardiovascular, hepatic, coagulation, renal and neurological systems), and scored from 0 (normal) to 4 (high degree of dysfunction/failure). Thus, the maximum score may range from 0 to 24.	baseline, during treatment (cycle 1 and 2 every 12 hours) up to 1 month
Number of participants with treatment-related side effects as assessed by Common Terminology Criteria for Adverse Event (CTCAE) version 5.0	graded according to CTCAE citeria (v5.0)	during treatment and up to 30 days after the last treatment dose
Radiological response	Thoracic CT scan or Chest XR	at baseline (optional), after seven days and if clinically indicated (up to 1 month)
Duration of hospitalization	Days of hospitalization	from baseline up to patient's discharge (up to 1 month)
Remission of respiratory symptoms	time to invasive mechanical ventilation (if not previously initiated) calculated from baseline to intubation	up to 1 month
Remission of respiratory symptoms	time to definitive extubation calculated from intubation (any time occurred) to extubation in days	up to 1 month
Remission of respiratory symptoms	time to independence from non-invasive mechanical ventilation calculated in days	up to 1 month
Remission of respiratory symptoms	time to independence from oxygen therapy in days	up to 1 month

Collaborators and Investigators

• Sponsor: National Cancer Institute, Naples
• Investigators: Principal Investigator: Francesco Perrone, MD, PhD, Istituto Nazionale Tumori IRCCS - Fondazione G. Pascale

Publications and helpful links

General Publications

• Perrone F, Piccirillo MC, Ascierto PA, Salvarani C, Parrella R, Marata AM, Popoli P, Ferraris L, Marrocco-Trischitta MM, Ripamonti D, Binda F, Bonfanti P, Squillace N, Castelli F, Muiesan ML, Lichtner M, Calzetti C, Salerno ND, Atripaldi L, Cascella M, Costantini M, Dolci G, Facciolongo NC, Fraganza F, Massari M, Montesarchio V, Mussini C, Negri EA, Botti G, Cardone C, Gargiulo P, Gravina A, Schettino C, Arenare L, Chiodini P, Gallo C; TOCIVID-19 investigators, Italy. Tocilizumab for patients with COVID-19 pneumonia. The single-arm TOCIVID-19 prospective trial. J Transl Med. 2020 Oct 21;18(1):405. doi: 10.1186/s12967-020-02573-9. Erratum In: J Transl Med. 2021 Oct 21;19(1):442.
• Chiodini P, Arenare L, Piccirillo MC, Perrone F, Gallo C. A phase 2, open label, multicenter, single arm study of tocilizumab on the efficacy and tolerability of tocilizumab in the treatment of patients with COVID-19 pneumonia (TOCIVID-19 trial): Statistical analysis plan. Contemp Clin Trials Commun. 2020 Dec;20:100665. doi: 10.1016/j.conctc.2020.100665. Epub 2020 Oct 7.
• Piccirillo MC, Ascierto P, Atripaldi L, Cascella M, Costantini M, Dolci G, Facciolongo N, Fraganza F, Marata A, Massari M, Montesarchio V, Mussini C, Negri EA, Parrella R, Popoli P, Botti G, Arenare L, Chiodini P, Gallo C, Salvarani C, Perrone F. TOCIVID-19 - A multicenter study on the efficacy and tolerability of tocilizumab in the treatment of patients with COVID-19 pneumonia. Study protocol. Contemp Clin Trials. 2020 Nov;98:106165. doi: 10.1016/j.cct.2020.106165. Epub 2020 Oct 6.

Study record dates

Study Major Dates

• Study Start (Actual): March 19, 2020
• Primary Completion (Anticipated): December 19, 2023
• Study Completion (Anticipated): December 19, 2023

Study Registration Dates

• First Submitted: March 19, 2020
• First Submitted That Met QC Criteria: March 19, 2020
• First Posted (Actual): March 20, 2020

Study Record Updates

• Last Update Posted (Actual): March 24, 2023
• Last Update Submitted That Met QC Criteria: March 23, 2023
• Last Verified: March 1, 2023

More Information

Terms related to this study

• Keywords: COVID-19; pneumonia; tocilizumab; Interleukin-6
• 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: TOCIVID-19; 2020-001110-38 (EudraCT Number)

Plan for Individual participant data (IPD)

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

IPD Plan Description

Data will be shared upon reasonable request to the Principal Investigator of the study

The following IPD will be available for sharing:

1. Baseline characteristics of patients
2. Treatment data
3. Safety data
4. Follow-up data

• IPD Sharing Time Frame: After peer-reviewed publication of the primary results, with no time limits
• IPD Sharing Access Criteria: Motivated requests to access to IPD are to be sent by email to the Principal Investigator (f.perrone@istitutotumori.na.it)
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP

Drug and device information, study documents

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