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

Primary Purpose

COVID-19 Pneumonia

Status
Active
Phase
Phase 2
Locations
Italy
Study Type
Interventional
Intervention
Tocilizumab Injection
Sponsored by
National Cancer Institute, Naples
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for COVID-19 Pneumonia focused on measuring COVID-19, pneumonia, tocilizumab, Interleukin-6

Eligibility Criteria

undefined - undefined (Child, Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

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

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

tocilizumab treatment

Arm Description

All the patients enrolled are treated with tocilizumab.

Outcomes

Primary Outcome Measures

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.
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.

Secondary Outcome Measures

Interleukin-6 level
IL-6 levels will be assessed using commercial ELISA method.
Lymphocyte count
Lymphocyte count assessed by routinely used determination of blood count
CRP (C-reactive protein) level
CRP is assessed by routinely used determination of CRP
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)
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.
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)
Radiological response
Thoracic CT scan or Chest XR
Duration of hospitalization
Days of hospitalization
Remission of respiratory symptoms
time to invasive mechanical ventilation (if not previously initiated) calculated from baseline to intubation
Remission of respiratory symptoms
time to definitive extubation calculated from intubation (any time occurred) to extubation in days
Remission of respiratory symptoms
time to independence from non-invasive mechanical ventilation calculated in days
Remission of respiratory symptoms
time to independence from oxygen therapy in days

Full Information

First Posted
March 19, 2020
Last Updated
March 23, 2023
Sponsor
National Cancer Institute, Naples
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1. Study Identification

Unique Protocol Identification Number
NCT04317092
Brief Title
Tocilizumab in COVID-19 Pneumonia (TOCIVID-19)
Acronym
TOCIVID-19
Official Title
Multicenter Study on the Efficacy and Tolerability of Tocilizumab in the Treatment of Patients With COVID-19 Pneumonia
Study Type
Interventional

2. Study Status

Record Verification Date
March 2023
Overall Recruitment Status
Active, not recruiting
Study Start Date
March 19, 2020 (Actual)
Primary Completion Date
December 19, 2023 (Anticipated)
Study Completion Date
December 19, 2023 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
National Cancer Institute, Naples

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
This study project includes a single-arm phase 2 study and a parallel cohort study, enrolling patients with COVID-19 pneumonia.
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: emergency conditions or infrastructural or operational limits prevented registration before the administration of the experimental drug or they had been intubated more than 24 hours before registration or 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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
COVID-19 Pneumonia
Keywords
COVID-19, pneumonia, tocilizumab, Interleukin-6

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Model Description
This is a multicenter, single-arm, open-label, phase 2 study. All the patients enrolled are treated with tocilizumab
Masking
None (Open Label)
Allocation
N/A
Enrollment
402 (Actual)

8. Arms, Groups, and Interventions

Arm Title
tocilizumab treatment
Arm Type
Experimental
Arm Description
All the patients enrolled are treated with tocilizumab.
Intervention Type
Drug
Intervention Name(s)
Tocilizumab Injection
Intervention Description
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.
Primary Outcome Measure Information:
Title
Lethality rate two weeks after registration
Description
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.
Time Frame
up to 15 days
Title
Lethality rate one month after registration
Description
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.
Time Frame
up to 1 month
Secondary Outcome Measure Information:
Title
Interleukin-6 level
Description
IL-6 levels will be assessed using commercial ELISA method.
Time Frame
baseline, during treatment (cycle 1 and 2 every 12 hours) up to 1 month
Title
Lymphocyte count
Description
Lymphocyte count assessed by routinely used determination of blood count
Time Frame
baseline, during treatment (cycle 1 and 2 every 12 hours) up to 1 month
Title
CRP (C-reactive protein) level
Description
CRP is assessed by routinely used determination of CRP
Time Frame
baseline, during treatment (cycle 1 and 2 every 12 hours) up to 1 month
Title
PaO2 (partial pressure of oxygen) / FiO2 (fraction of inspired oxygen, FiO2) ratio (or P/F ratio)
Description
calculated from arterial blood gas analyses (values from 300 to 100)
Time Frame
baseline, during treatment (cycle 1 and 2 every 12 hours) up to 1 month
Title
Change of the SOFA (Sequential Organ Failure Assessment)
Description
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.
Time Frame
baseline, during treatment (cycle 1 and 2 every 12 hours) up to 1 month
Title
Number of participants with treatment-related side effects as assessed by Common Terminology Criteria for Adverse Event (CTCAE) version 5.0
Description
graded according to CTCAE citeria (v5.0)
Time Frame
during treatment and up to 30 days after the last treatment dose
Title
Radiological response
Description
Thoracic CT scan or Chest XR
Time Frame
at baseline (optional), after seven days and if clinically indicated (up to 1 month)
Title
Duration of hospitalization
Description
Days of hospitalization
Time Frame
from baseline up to patient's discharge (up to 1 month)
Title
Remission of respiratory symptoms
Description
time to invasive mechanical ventilation (if not previously initiated) calculated from baseline to intubation
Time Frame
up to 1 month
Title
Remission of respiratory symptoms
Description
time to definitive extubation calculated from intubation (any time occurred) to extubation in days
Time Frame
up to 1 month
Title
Remission of respiratory symptoms
Description
time to independence from non-invasive mechanical ventilation calculated in days
Time Frame
up to 1 month
Title
Remission of respiratory symptoms
Description
time to independence from oxygen therapy in days
Time Frame
up to 1 month

10. Eligibility

Sex
All
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Any gender No age limit 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) Virological diagnosis of SARS-CoV-2 infection (real-time PCR) Hospitalized due to clinical/instrumental diagnosis of pneumonia Oxygen saturation at rest in ambient air ≤93% or requiring oxygen therapy or mechanical ventilation either non invasive or invasive (intubated) Patients with criteria #4 and #5 who have been already treated with tocilizumab before registration are eligible for the observational retrospective cohort Exclusion Criteria: Known hypersensitivity to tocilizumab or its excipients Known active infections or other clinical condition that contraindicate tocilizumab and cannot be treated or solved according to the judgement of the clinician ALT / AST> 5 times the upper limit of the normality Neutrophils <500 / mmc Platelets <50.000 / mmc Bowel diverticulitis or perforation
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Francesco Perrone, MD, PhD
Organizational Affiliation
Istituto Nazionale Tumori IRCCS - Fondazione G. Pascale
Official's Role
Principal Investigator
Facility Information:
Facility Name
Azienda Ospedaliera "SS. Antonio e Biagio e C. Arrigo" (Dipartimento Internistico SSD Reumatologia)
City
Alessandria
Country
Italy
Facility Name
Ospedale di Busto Arsizio ASST Valle Olona (U.O.C. Malattie Infettive)
City
Busto Arsizio
Country
Italy
Facility Name
A.O.U. Policlinico V. Emanuele (U.O. di Malattie infettive, U.O. di Anestesia e Rianimazione, U.O. di Medicina d'Urgenza)
City
Catania
Country
Italy
Facility Name
AOE Cannizzaro di Catania (U.O. di Malattie Infettive, U.O. di Anestesia e Rianimazione, U.O.
City
Catania
Country
Italy
Facility Name
Ospedale Annunziata Azienda Ospedaliera di Cosenza (U.O.C. Malattie Infettive)
City
Cosenza
Country
Italy
Facility Name
ASST OVEST MILANESE presidi Legnano - Magenta
City
Magenta
Country
Italy
Facility Name
Azienda Ospedaliero-Universitaria di Modena
City
Modena
ZIP/Postal Code
42100
Country
Italy
Facility Name
A.O.U. di Modena (Dipartimento Chirurgie Generali e Specialità Chirurgiche - Struttura Complessa di Anestesia e Rianimazione I)
City
Modena
Country
Italy
Facility Name
A.O.U. di Modena (Dipartimento Chirurgie Generali e Specialità Chirurgiche - Struttura Complessa di Anestesia e Rianimazione II)
City
Modena
Country
Italy
Facility Name
A.O.U. di Modena (Dipartimento Medicine Specialistiche - Struttura Complessa Malattie Infettive)
City
Modena
Country
Italy
Facility Name
Dipartimento Medicine Specialistiche - Struttura Complessa Malattie dell'Apparato Respiratorio
City
Modena
Country
Italy
Facility Name
A.O.R.N. Ospedale dei Colli Monaldi-Cotugno-CTO (U.O.C. Oncologia)
City
Naples
ZIP/Postal Code
80131
Country
Italy
Facility Name
National Cancer Institute
City
Naples
ZIP/Postal Code
80131
Country
Italy
Facility Name
A.O.R.N. Ospedale dei Colli Monaldi-Cotugno-CTO (U.O.C. Anestesia Rianimazione e terapia intensiva)
City
Naples
Country
Italy
Facility Name
A.O.R.N. Ospedale dei Colli Monaldi-Cotugno-CTO (U.O.C. Malattie Infettive ad indirizzo respiratorio)
City
Naples
Country
Italy
Facility Name
A.O. Ospedali Riuniti Marche Nord - Presidio Ospedaliero San Salvatore di Pesaro (UOC Pronto Soccorso e Medicina d'Urgenza)
City
Pesaro
Country
Italy
Facility Name
Denominazione: UOC di Medicina e Chirurgia d'Accettazione e d'Urgenza dell'Ospedale Santa Maria delle Grazie di Pozzuoli
City
Pozzuoli
Country
Italy
Facility Name
Ospedale Santa Maria delle Croci, AUSL della Romagna (U.O. Anestesia e Rianimazione)
City
Ravenna
Country
Italy
Facility Name
Grande Ospedale Metropolitano, Reggio Calabria
City
Reggio Calabria
Country
Italy
Facility Name
Ospedale Infermi, AUSL della Romagna (U.O. Malattie Infettive)
City
Rimini
Country
Italy
Facility Name
Policlinico Gemelli (U.O.C. Dipartimento Scienze di Laboratorio e Infettivologiche)
City
Rome
Country
Italy
Facility Name
ASST Sette Laghi (Dipartimento di Medicina Interna)
City
Varese
Country
Italy
Facility Name
ASST Sette Laghi (Dipartimento Emergenze ed Urgenze)
City
Varese
Country
Italy
Facility Name
ASST Sette Laghi (U.O.C. Anestesia e Rianimazione Neurochirurgica e Generale)
City
Varese
Country
Italy
Facility Name
ASST Sette Laghi (U.O.C. Malattie Infettive e Tropicali)
City
Varese
Country
Italy
Facility Name
A.O.U. Integrata di Verona (Dip. Malattie Infettive)
City
Verona
Country
Italy
Facility Name
Ospedale Magalini (U.O. Malattie Infettive)
City
Villafranca Di Verona
Country
Italy

12. IPD Sharing Statement

Plan to Share IPD
Yes
IPD Sharing Plan Description
Data will be shared upon reasonable request to the Principal Investigator of the study The following IPD will be available for sharing: Baseline characteristics of patients Treatment data Safety data 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)
Citations:
PubMed Identifier
33087150
Citation
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.
Results Reference
derived
PubMed Identifier
33043164
Citation
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.
Results Reference
derived
PubMed Identifier
33031955
Citation
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.
Results Reference
derived

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Tocilizumab in COVID-19 Pneumonia (TOCIVID-19)

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