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

• ClinicalTrials.gov Identifier: NCT04317092
• Recruitment Status: Active, not recruiting
• First Posted: March 20, 2020
• Last Update Posted: March 24, 2023
• Sponsor: National Cancer Institute, Naples
• Information provided by (Responsible Party): National Cancer Institute, Naples

Tracking Information

• First Submitted Date: March 19, 2020
• First Posted Date: March 20, 2020
• Last Update Posted Date: March 24, 2023
• Actual Study Start Date: March 19, 2020
• Estimated Primary Completion Date: December 19, 2023 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: October 19, 2020)

• Lethality rate two weeks after registration [ Time Frame: up to 15 days ]
  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 [ Time Frame: up to 1 month ]
  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.

Original Primary Outcome Measures (submitted: March 19, 2020)

One-month mortality rate [ Time Frame: up to 1 month ]

1-month mortality is defined as the ratio of patients who will alive after 1month from study start out of those registered at baseline

Current Secondary Outcome Measures (submitted: March 19, 2020)

• Interleukin-6 level [ Time Frame: baseline, during treatment (cycle 1 and 2 every 12 hours) up to 1 month ]
  IL-6 levels will be assessed using commercial ELISA method.
• Lymphocyte count [ Time Frame: baseline, during treatment (cycle 1 and 2 every 12 hours) up to 1 month ]
  Lymphocyte count assessed by routinely used determination of blood count
• CRP (C-reactive protein) level [ Time Frame: baseline, during treatment (cycle 1 and 2 every 12 hours) up to 1 month ]
  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) [ Time Frame: baseline, during treatment (cycle 1 and 2 every 12 hours) up to 1 month ]
  calculated from arterial blood gas analyses (values from 300 to 100)
• Change of the SOFA (Sequential Organ Failure Assessment) [ Time Frame: baseline, during treatment (cycle 1 and 2 every 12 hours) up to 1 month ]
  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 [ Time Frame: during treatment and up to 30 days after the last treatment dose ]
  graded according to CTCAE citeria (v5.0)
• Radiological response [ Time Frame: at baseline (optional), after seven days and if clinically indicated (up to 1 month) ]
  Thoracic CT scan or Chest XR
• Duration of hospitalization [ Time Frame: from baseline up to patient's discharge (up to 1 month) ]
  Days of hospitalization
• Remission of respiratory symptoms [ Time Frame: up to 1 month ]
  time to invasive mechanical ventilation (if not previously initiated) calculated from baseline to intubation
• Remission of respiratory symptoms [ Time Frame: up to 1 month ]
  time to definitive extubation calculated from intubation (any time occurred) to extubation in days
• Remission of respiratory symptoms [ Time Frame: up to 1 month ]
  time to independence from non-invasive mechanical ventilation calculated in days
• Remission of respiratory symptoms [ Time Frame: up to 1 month ]
  time to independence from oxygen therapy in days

• 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: Tocilizumab in COVID-19 Pneumonia (TOCIVID-19)
• Official Title: Multicenter Study on the Efficacy and Tolerability of Tocilizumab in the Treatment of Patients With COVID-19 Pneumonia
• 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:

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
• Study Phase: Phase 2

Study Design

Allocation: N/A
Intervention Model: Single Group Assignment
Intervention 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)
Primary Purpose: Treatment

• Condition: COVID-19 Pneumonia

Intervention

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.

Study Arms

Experimental: tocilizumab treatment

All the patients enrolled are treated with tocilizumab.

Intervention: Drug: Tocilizumab Injection

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.

Recruitment Information

• Recruitment Status: Active, not recruiting
• Actual Enrollment (submitted: March 2, 2021): 402
• Original Estimated Enrollment (submitted: March 19, 2020): 330
• Estimated Study Completion Date: December 19, 2023
• Estimated Primary Completion Date: December 19, 2023 (Final data collection date for primary outcome measure)

Eligibility Criteria

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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: Child, 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: NCT04317092
• Other Study ID Numbers: TOCIVID-19; 2020-001110-38 ( 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

IPD Sharing Statement

• Plan to Share IPD: Yes

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

• Supporting Materials: Study Protocol
• Supporting Materials: Statistical Analysis Plan (SAP)
• Time Frame: After peer-reviewed publication of the primary results, with no time limits
• Access Criteria: Motivated requests to access to IPD are to be sent by email to the Principal Investigator (f.perrone@istitutotumori.na.it)

• Current Responsible Party: National Cancer Institute, Naples
• Original Responsible Party: Same as current
• Current Study Sponsor: National Cancer Institute, Naples
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Principal Investigator: Francesco Perrone, MD, PhD; Istituto Nazionale Tumori IRCCS - Fondazione G. Pascale

• PRS Account: National Cancer Institute, Naples
• Verification Date: March 2023