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A Multicenter, Randomized, Open-Label, Phase II Trial to Evaluate the Efficacy and Safety of Checkpoint Blockade in Patients With Coronavirus Disease 2019 (COVID-19)-Related Mild Acute Respiratory Syndrome Nonresponsive to Frontline Therapy

Trial Profile

A Multicenter, Randomized, Open-Label, Phase II Trial to Evaluate the Efficacy and Safety of Checkpoint Blockade in Patients With Coronavirus Disease 2019 (COVID-19)-Related Mild Acute Respiratory Syndrome Nonresponsive to Frontline Therapy

Status: Recruiting
Phase of Trial: Phase II

Latest Information Update: 05 Jun 2020

At a glance

  • Drugs Pembrolizumab (Primary) ; Tocilizumab (Primary)
  • Indications COVID 2019 infections; Pneumonia; Severe acute respiratory syndrome
  • Focus Therapeutic Use
  • Acronyms COPERNICO
  • Most Recent Events

    • 02 Jun 2020 Planned initiation date (estimated date for recruitment of the first subject) changed from 29 May 2020 to 1 Jul 2020.
    • 02 Jun 2020 Planned End Date changed from 30 Jun 2020 to 30 Aug 2020.
    • 02 Jun 2020 Planned primary completion date changed from 30 Jun 2020 to 30 Aug 2020.

Trial Overview

Purpose

This is a prospective, multicenter, randomized, controlled, open-label, phase 2 clinical trial. The aim of this study is to evaluate the efficacy of tocilizumab combined with pembrolizumab (MK-3475) compared to standard care in adult patients with COVID-19 pneumonia and bad prognostic factors who are nonresponsive to frontline therapy within 48 hours from treatment initiation.

Primary Endpoints

Percentage of patients with normalization of SpO2 ≥96%

description: Assessed by hospital records
time_frame: through day 14 after study treatment initiation

Other Endpoints

Proportion of patients with temperature < 37,5 °C armpit.

description: Assessed by hospital records time_frame: through day 14 after study treatment initiation

Proportion of patients discharged from the emergency department and classified as low risk

description: Assessed by hospital records time_frame: In less than 28 days

Change from baseline in organ failure parameters

description: The clinical status will be assessed by the SOFA scores time_frame: Days 1, 3, 5, 7, 14 (+/- 1 day) and 28 (+/- 2 days) or until discharge whatever it comes first.

Proportion of mortality rate

description: Determined as percentage of dead patients time_frame: Day 28

Analysis of the remission of respiratory symptoms

description: Determined as: Time to invasive mechanical ventilation (if not previously initiated); Time to independence from non-invasive mechanical ventilation; Time to independence from oxygen therapy. time_frame: Up to 3 months after last dose of treatment

Evaluation of the radiological response

description: by using the same imaging technique (chest X-ray or thoracic CT scan) time_frame: at days 1 and 28 (+/- 2 days)

Time to first negative in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RT-PCR test

description: determined using oropharyngeal or anal swabs time_frame: within 28 days from study inclusion

Change from baseline of absolute lymphocyte count (ALC),white blood cell count and white blood cell differential count

description: Baseline defined as the value collected at day 1, 2 hours before treatment administration time_frame: days 3, 5, 7, 10, 14 and 28 after administration of study drug

Change from baseline of hemoglobin

description: Baseline defined as the value collected at day 1, 2 hours before treatment administration time_frame: days 3, 5, 7, 10, 14 and 28 after administration of study drug

Change from baseline of platelets

description: Baseline defined as the value collected at day 1, 2 hours before treatment administration time_frame: days 3, 5, 7, 10, 14 and 28 after administration of study drug

Change from baseline of activated partial thromboplastin time (aPTT)

description: Baseline defined as the value collected at day 1, 2 hours before treatment administration time_frame: days 3, 5, 7, 10, 14 and 28 after administration of study drug

Change from baseline of Alanine Aminotransferase (ALT) and Aspartate Aminotransferase (AST)

description: Baseline defined as the value collected at day 1, 2 hours before treatment administration time_frame: days 3, 5, 7, 10, 14 and 28 after administration of study drug

Change from baseline of creatinine

description: Baseline defined as the value collected at day 1, 2 hours before treatment administration time_frame: days 3, 5, 7, 10, 14 and 28 after administration of study drug

Change from baseline of glucose

description: Baseline defined as the value collected at day 1, 2 hours before treatment administration time_frame: days 3, 5, 7, 10, 14 and 28 after administration of study drug

Change from baseline of total bilirubin

description: Baseline defined as the value collected at day 1, 2 hours before treatment administration time_frame: days 3, 5, 7, 10, 14 and 28 after administration of study drug

Change from baseline of albumin

description: Baseline defined as the value collected at day 1, 2 hours before treatment administration time_frame: days 3, 5, 7, 10, 14 and 28 after administration of study drug

Incidence of adverse events (AEs), incidence of prespecified AEs (safety and tolerability)

description: Evaluated using the Common Terminology Criteria for Adverse Events version 5.0 (CTCAE v.5.0), SOFA scores. time_frame: Up to 28 days after last dose of treatment [1]

Diseases Treated

Indication Qualifiers Patient Segments
COVID 2019 infections treatment -
Pneumonia treatment previously treated
Severe acute respiratory syndrome treatment -

Subjects

  • Subject Type patients
  • Number

    Planned: 24

  • Sex male & female
  • Age Group ≥ 18 years; adult; elderly

Patient Inclusion Criteria

1. Signed informed consent form (ICF) prior to participation in any study-related activities. 2. Male or nonpregnant female patients ≥ 18 years at the time of signing ICF. 3. Laboratory confirmed COVID-19 infection defined with a positive reverse transcription-polymerase chain reaction (RT-PCR) from any specimen and/or detection of SARS-CoV-2 immunoglobulin (Ig) M / Ig G antibodies. 4. Diagnostic confirmation of pneumonia by either chest X-ray or thoracic CT scan (preferable). 5. Patient with severe acute respiratory syndrome related to COVID-19 under treatment as per hospital protocol during at least 48 hours. 6. Patients with Sequential Organ Failure Assessment (SOFA) score ≤ 3 at the time of signing ICF. 7. Patients hospitalized with fever defined as temperature ≥ 37,5 °C armpit. 8. Patients with total lymphocyte count ≤0,8 x106/mL. 9. Patients who are showing SpO2 ≤ 92% on room air and/or patient who are showing SpO2 ≤ 94% on room air and meet at least one of the following parameters: - No objective clinical improvement at physician's discretion after 48 hours of front-line standard care for COVID-19; - Decrease in lymphocyte count (any decrease within 48 hours); - Increase in ferritin levels (any increase within 48 hours); - Increase in interleukin-6 (IL-6) levels (any increase within 48 hours); - Increase in D-dimer levels (any increase within 48 hours); - Increase in C-Reactive Protein (CRP) levels (any increase within 48 hours); - Increase in lactate dehydrogenase (LDH) levels (any increase within 48 hours); - Increase in erythrocyte sedimentation rate(ESR) levels (any increase within 48 hours). 10. Life expectancy greater than 10 days. 11. Willing to take study medication and to comply with all study procedures. 12. In women of childbearing potential, negative pregnancy test and commitment to use contraceptive method throughout the study.

Patient Exclusion Criteria

1. Participation in any other clinical trial of an experimental treatment for COVID-19. 2. Concurrent treatment with other agents with actual or possible direct acting antiviral activity against SARS-CoV-2 is prohibited < 24 hours prior to study drug dosing, except the commonly used antiviral drugs and/or chloroquine. 3. Requiring endotracheal intubation, mechanical ventilation, and extracorporeal membrane oxygenation (ECMO) at screening. 4. Patients being treated with immunomodulators or anti-rejection drugs. 5. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 5 x upper limit of normal (ULN). 6. Creatinine clearance < 50 mL/min. 7. Chronic Obstructive Pulmonary Disease (COPD) or end-stage lung disease that require home oxygen therapy. 8. Known hypersensitivity to recombinant proteins, or any excipient contained in the drug formulation of study pembrolizumab and tocilizumab. 9. Treatment with high doses of systemic corticosteroids within 72 hours prior signing the ICF except for inhaled steroids and prior corticosteroid therapy at dose lower than or equal to 10 mg/day methylprednisolone equivalent. 10. Bowel diverticulitis or perforation. 11. Diagnosis of immunodeficiency receiving immunosuppressive therapy within seven days prior to study treatment initiation. Active autoimmune disease that has required systemic treatment in past 2 years (i.e., with use of disease modifying agents, corticosteroids, or immunosuppressive drugs). 12. Current known infection with human immunodeficiency virus (HIV), hepatitis B virus (HBV), or hepatitis C virus (HCV). Patients with past HBV infection or resolved HBV infection (defined as having a negative hepatitis B surface antigen [HBsAg] test and a positive hepatitis B core antibody [HBcAb] test, accompanied by a negative HBV DNA test) are eligible. Patients positive for HCV antibody are eligible only if polymerase chain reaction (PCR) is negative for HCV ribonucleic acid (RNA). 13. Vaccination with any live virus vaccine within 28 days prior to study treatment initiation. Note: Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, chicken pox/zoster, yellow fever, rabies, Bacillus Calmette-Guérin (BCG), and typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (e.g., FluMist®) are live-attenuated vaccines and are not allowed. 14. History of prior allogeneic bone marrow, stem-cell, or solid organ transplantation. 15. Patients have any other concurrent severe medical condition that would, in the Investigator's judgment contraindicate patient participation in the clinical study. 16. Pregnant women, lactating women and planned pregnant women.

Trial Details

Identifiers

Identifier Owner
NCT04335305 ClinicalTrials.gov: US National Institutes of Health
EudraCT2020-001160-28 European Clinical Trials Database
MedOPP376 -

Trial Dates

  • Initiation Dates

    Planned : 01 Jul 2020

  • Primary Completion Dates

    Planned : 30 Aug 2020

  • End Dates

    Planned : 30 Aug 2020

Other Details

  • Design multicentre; open; parallel; prospective; randomised
  • Phase of Trial Phase II
  • Location Spain
  • Focus Therapeutic Use

Interventions

Drugs Route Formulation
PembrolizumabPrimary Drug Intravenous Infusion
TocilizumabPrimary Drug Intravenous Infusion

Tocilizumab plus Pembrolizumab (MK-3475)

Tocilizumab 8 mg/kg (up to a maximum of 800 mg per dose) as an intravenous infusion over 60 minutes; single dose Pembrolizumab (MK3475) 200 mg as an intravenous infusion over 30 minutes; single dose.
Patients who are showing no clinical improvement in respiratory function after 12 hours could receive an additional dose of tocilizumab at the same dose level of the first administration. Patients who are showing SpO2 ≤ 94% on room air could receive an additional administration of pembrolizumab (MK-3475) at the same recommended dose after 3 weeks from treatment initiation and/or an additional dose of tocilizumab after 4 weeks from treatment initiation at physician's discretion.
Drug: Tocilizumab (IV infusion over 60 minutes; 8 mg/kg (up to a maximum of 800 mg per dose); single dose) Other Name: Actemra, RoActemra
Biological: Pembrolizumab (MK-3475) (IV infusion over 30 minutes, 200 mg; single dose) Other Name: MK-3475, Keytruda

Continued Standard of Care

Standard care per local written policies or guidelines comprises, as necessary and at physician's discretion, supplemental oxygen, noninvasive and invasive ventilation, antibiotic agents, vasopressor support, renal-replacement therapy, glucocorticoid, tocilizumab, virally targeted agents, chloroquine or hydroxychloroquine.

Trial Centres

Investigators

Investigator Centre Name Trial Centre Country
Alicia García
+34 611 261 467 alicia.garcia@medsir.org
show details
-
Arturo Artero, MD Hospital Universitario Doctor Peset Spain
Clinical Trial Unit
Torre Glòries. Avenida Diagonal, 211, planta 27,
Barcelona, 08018, Spain
34932214135
regulatory@medsir.org
show details
Medica Scientia Innovation Research S.L. (MEDSIR) Spain
Fernando Cereto, MD Hospital Quirónsalud Barcelona Spain
Javier Cortés IOB Institute of Oncology, Vall d´Hebron Institute of Oncology (VHIO)
-
Javier Ignacio Taboada, MD Hospital Ruber Internacional Spain
Jesús Caballero, MD Hospital Universitari Arnau de Vilanova de Lleida Spain
Juan Flores Cid, MD Hospital Arnau de Vilanova-Lliria Spain
María Pilar Martialay, MD Hospital Ruber Juan Bravo Spain
Matilde Sánchez, MD Hospital Universitario Ramón y Cajal Spain

Centres

Centre Name Location Trial Centre Country
-
-
-
Hospital Arnau de Vilanova-Lliria Valencia Spain
Hospital de la Santa Creu i Sant Pau Barcelona Spain
Hospital Quirónsalud Barcelona Barcelona Spain
Hospital Ruber Internacional Madrid Spain
Hospital Ruber Juan Bravo Madrid Spain
Hospital Universitari Arnau de Vilanova de Lleida Lleida Spain
Hospital Universitario Doctor Peset Valencia Spain
Hospital Universitario Ramón y Cajal Madrid Spain
IOB Institute of Oncology, Vall d´Hebron Institute of Oncology (VHIO)
-
-
Medica Scientia Innovation Research S.L. (MEDSIR) Barcelona Spain
MedSIR
-
-

Trial History

Event Date Event Type Comment
05 Jun 2020 Other trial event Last checked against ClinicalTrials.gov record. Updated 05 Jun 2020
02 Jun 2020 Other trial event Planned initiation date (estimated date for recruitment of the first subject) changed from 29 May 2020 to 1 Jul 2020. Updated 05 Jun 2020
02 Jun 2020 Completion date Planned End Date changed from 30 Jun 2020 to 30 Aug 2020. Updated 05 Jun 2020
02 Jun 2020 Other trial event Planned primary completion date changed from 30 Jun 2020 to 30 Aug 2020. Updated 05 Jun 2020
18 May 2020 Other trial event Planned initiation date (estimated date for recruitment of the first subject) changed from 14 Apr 2020 to 29 May 2020. Updated 05 Jun 2020
18 May 2020 Completion date Planned End Date changed from 15 May 2020 to 30 Jun 2020. Updated 20 May 2020
18 May 2020 Other trial event Planned primary completion date changed from 15 May 2020 to 30 Jun 2020. Updated 20 May 2020
17 Apr 2020 Other trial event New source identified and integrated (European Clinical Trials Database; EudraCT2020-001160-28) Updated 17 Apr 2020
14 Apr 2020 Other trial event Planned initiation date (estimated date of first participant enrollement) changed from 30 Mar 2020 to 14 Apr 2020. Updated 16 Apr 2020
14 Apr 2020 Status change - recruiting Status changed from not yet recruiting to recruiting. Updated 16 Apr 2020
08 Apr 2020 New trial record New trial record Updated 08 Apr 2020

References

  1. ClinicalTrials.gov: US National Institutes of Health. Trial-Reg 2016;.

    Available from: URL: http://clinicaltrials.gov
  2. European Clinical Trials Database. Trial-Reg 2016;.

    Available from: URL: https://www.clinicaltrialsregister.eu
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