Overview
The primary objective of the study is 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
Description
The study consists of two phases:
- Pilot phase: the first 189 patients will be randomized in three groups to receive OKZ, RPH-104 (63 patients per group). Early safety and efficacy analysis will be performed based on the results obtained in the pilot period to adjust sample size.
- Core phase: further enrollment of patients and performing all study procedures as per protocol.
After analyzing the data of the first 189 randomized patients, a decision will be made about the final sample size, so the minimal sample size will be 189 randomized patients, the maximal - 372 randomized patients.
The study will include the following periods:
- Screening period lasting up to 48 hours until the beginning of the Day 1. During this period patient's eligibility assessment will be performed;
- Treatment period lasting from the end of the screening (considered as the beginning of the Day 1) to 23:59 of the Day 1 will include randomization of the patients in the treatment groups following by administration of a single dose of the study drug;
- Follow-up period lasting from 00:00 of the Day 2 to 23:59 of the Day 29 will include efficacy and safety assessments after study drug administration.
Eligible patients will be 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 will be performed (Day 1 - Day 15 of the Last Hospitalization Day (LHD), whichever comes first). Then there will be follow-up period, lasting from Day 15 or LHD (whichever comes first) to Day 29.
Standard COVID-19 therapy, as per the institution routine practice, is 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 is 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.
At Day 15 primary endpoint of patient's clinical status (response to the study therapy) will be assessed. The response to the therapy will be 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 will be the visit on Day 29. If the patient is discharged from the hospital earlier than Day 15 or Day 29, patient's clinical status at these visits will be assessed by phone call.
Expected study duration for each patient will be 31 days, including 48 hours of screening, 1 day of study drug administration, and 28 days of follow-up.
Eligibility
Inclusion criteria:
- 1. Signed and dated patient's Informed consent for participation in this study, or record of a medical board 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 parameters SpO2 93% (on room air) or respiratory rate greater than 30/min;
- 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. Hypersensitivity to the study drugs (RPH-104 and/or OKZ), and/or its components.
- 2. 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 (to maintain mean arterial pressure 65 mm Hg and lactate 2 mmol/L in the absence of hypovolemia, vasopressors are necessary)
- 5. Progression of disease up to the death in the following 24 hours regardless of treatment, as per Investigator's opinion
- 6. History of perforation of gastrointestinal tract, history of diverticulitis
- 7. Plasma infusion from convalescent COVID-19 donors within 4 weeks prior to patient inclusion and/or planned infusion 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:
- immunosuppressive biologics over than OKZ or RPH-104, including but not limited, Interleukin-1 (IL-1) inhibitors (rilonacept, anakinra, canakinumab) , IL-6 inhibitors (except tocilizumab and sarilumab), IL-17A inhibitors (secukinumab),tumor necrosis factor (TNF) inhibitors (adalimumab, infliximab, etanercept), anti-B-cell therapy and others
- other immunosuppressors except methotrexate dosed up to 25 mg per week, including
but not limited:
- high-dose glucocorticoids ( > 1mg/kg of prednisolone equivalent), oral and parental;
- JAK inhibitors, cyclophosphamide, and others
- 10. Concurrent participation in another clinical trial.
- 11. Pregnancy or lactation
- 12. History of active tuberculosis, active tuberculosis suspected by Investigator