Recruitment issues

This is a prospective, multicenter, randomized, controlled, open-label, phase 2 clinical trial

The aim of this study is to assess the efficacy -as determined by the proportion of patients with normalization of SpO2 ≥96% on room air- of continued standard care together with tocilizumab plus pembrolizumab (MK- 3475) in patients with COVID-19 pneumonia

Inclusion Criteria:

1. Informed consent form (ICF) prior to participation in any study-related activities.

   Note: If no written ICF can be provided by the trial participant, consent could be given either orally in the presence of an impartial witness or from the legal representative in accordance with national and local patient regulations.

2. Male or non-pregnant female patients ≥ 18 years and ≤ 80 years at the time of 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/IgG antibodies.

4. Diagnostic confirmation of pneumonia by either chest X-ray or thoracic CT scan (preferable).

5. Patient with acute respiratory syndrome related to COVID-19.

6. Patients with Sequential Organ Failure Assessment (SOFA) score ≤ 3 at the time of ICF.

7. Patients with total lymphocyte count ≤0,8 x106/mL.

8. Patients who are showing SpO2 ≤ 92% on room air (measured without any respiratory support for at least 15 minutes). Note: For patients on prior tocilizumab-containing regimen, SpO2 ≤ 94% on room air is sufficient criterion for their eligibility.

9. Patients who meet at least one of the following parameters: • Increased levels of ferritin;

   • Increased levels of IL-6;
   • Increased levels of D-dimer;
   • Increased levels of CRP;
   • Increased levels of LDH;
   • Increased levels of ESR;
   • For patients on prior tocilizumab-containing regimen for COVID-19, no objective clinical improvement at physician's discretion within 48 hours after treatment initiation.

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.

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 and/or tocilizumab.

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 obtaining consent 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 PCR test 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.