Study of the Efficacy and Safety of a Single Administration of Olokizumab and RPH-104 With Standard Therapy in Patients With Severe Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Infection (COVID-19)

An International, Multicenter, Randomized, Double-blind, Adaptive Placebo-controlled Study of the Efficacy and Safety of a Single Administration of Olokizumab and RPH-104 With Standard Therapy in Patients With Severe SARS-CoV-2 Infection (COVID-19)

The primary objective of the study was to evaluate the efficacy and safety of a single dose of RPH-104 (80 mg) or OKZ (64 mg) compared to placebo in addition to standard therapy in patients with severe SARS-CoV-2 infection (COVID-19) at Day 15 of the study.

The study consisted of two phases:

• Pilot phase: the first 189 patients were randomized in three groups to receive OKZ, RPH-104 (63 patients per group), followed by an interim analysis of efficacy and safety data.
• The main phase was the conduct of all procedures prespecified in the protocol. Based on results of interim analysis no changes were made regarding the sample size or primary efficacy endpoint.

For each patient the study included the following periods:

• Screening period for no more than 48 hours before the start of the day of randomization (Day 1). During the screening period, an assessment was performed to determine whether the patient met the eligibility criteria;
• Treatment period lasting from the end of the screening (considered as the beginning of the Day 1) to 23:59 of the Day 1, including randomization of the patients in the treatment groups and then a single administration of the study drug;
• Follow-up period lasting from 00:00 of the Day 2 to 23:59 of the Day 29, including an assessment of the efficacy and safety after administration of the study drug.

Eligible patients were randomized to one of three treatment groups to receive a single subcutaneous injection: RPH-104 80 mg, OKZ 64 mg or placebo in addition to standard care for patients with COVID-19 as per the routine practice in participating facilities. Further, during the term of hospitalization, the clinical observation was performed (Day 1 - Day 15 of the Last Hospitalization Day (LHD), whichever comes first). This was followed by a follow-up period from the from Day 15 or LHD (whichever comes first) to Day 29.

Standard COVID-19 therapy, as per the institution routine practice, was permitted during the study, except the prohibited protocol medication (during the whole period of the study) and tocilizumab and sarilumab (during the first 24 hours after the study treatment administration).

In the absence of positive dynamics in the patient's condition (as per Investigator's judgement), it was possible to administrate a single dose of tocilizumab or sarilumab (in accordance with the actual recommendations), after the 24 hours from one of the study drug's administration.

On Day 15 primary endpoint of patient's clinical status (response to the study therapy) was assessed. The response to the therapy was considered as improvement of the patient's clinical status by at least 1 point on a 6-point COVID-19 scale in the absence of tocilizumab or sarilumab administration.

The last patient's visit in the study was the visit on Day 29. If the patient was discharged from the hospital earlier than Day 15 or Day 29, patient's clinical status at these visits were assessed by phone call.

The total expected duration of the study for each patient was not more than 31 days, including 48 hours of screening, 1 day of the study drug administration and 28 days of observation.

Inclusion criteria:

1. The presence of a voluntarily signed and dated Patient Informed Consent Form for participation in this study, or a record of an Medical Consilium decision justifying patient's participation in case of patient is unable to state his/her will.

2. Having either of the following COVID-associated respiratory syndromes:

   • pneumonia with oxygenation saturation SpO2 ≤93% (on room air) or respiratory rate greater than 30/min;
   • Acute respiratory distress syndrome (ARDS) ( PaO2/FiO2 ≤ 300 mmHg or SpO2/FiO2 ≤ 315 if PaO2 is not available).

3. COVID-19 diagnosis based on:

   • laboratory-confirmed SARS-CoV-2 infection as determined by Polymerase Chain Reaction method (PCR).

OR

• Bilateral changes in the lungs typical for COVID-19, based on chest computed tomography results.

Exclusion criteria:

1. A history of hypersensitivity to the study drugs (RPH-104 and/or OKZ), and/or their components.

2. The presence of any of the following laboratory abnormalities:

   • absolute neutrophil counts < 0.5 x 10^9 L
   • white blood cell count < 2 x 10^9 L
   • platelet count <50 x 10^9 L
   • Alanine aminotransferase (ALT) and/or Aspartate aminotransferase (AST) ≥ 3.0 x Upper Limit of Normal (ULN)

3. Severe renal failure: creatinine clearance < 30 mL/min

4. Septic shock (vasopressors are required to maintain mean arterial pressure ≥ 65 mm Hg and lactate ≥ 2 mmol/L in the absence of hypovolemia)

5. The disease progresses to death over the next 24 hours, regardless of treatment, according to Investigator.

6. Perforation of the gastrointestinal tract, a history of diverticulitis.

7. Administration of plasma from COVID-19 convalescent donors within 4 weeks before study enrollment and/or planned administration during the study.

8. Recent (less then 5 half-lives) administration of tocilizumab or sarilumab;

9. Recent (less then 5 half-lives) or planned during the current study period use of the following drugs:

   • biologics (except RPH-104 or OKZ) with immunosuppressive effect, including, but not limited to: Interleukin-1 (IL-1) inhibitors (anakinra, rilonacept, canakinumab), IL- 6 inhibitors (except tocilizumab and sarilumab), IL-17A inhibitors (secukinumab), tumor necrosis factor α (TNFα) inhibitors (infliximab, adalimumab, etanercept, etc.), antiB-cell drugs, etc.

   • other immunosuppressive drugs (with the exception of methotrexate in a dose of up to 25 mg/week), including, but not limited to:

     1. high doses of glucocorticoids (equivalent to prednisolone > 1 mg/kg) orally or parenterally;
     2. Janus kinase (JAK) kinase inhibitors; cyclophosphamide, etc.

10. Concurrent participation in another clinical trial.

11. Pregnancy, breastfeeding.

12. A history of active tuberculosis, or active tuberculosis suspected by the Investigator.