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.

Study Overview

• Status: Completed
• Conditions: COVID-19
• Intervention / Treatment: Drug: Placebo; Drug: RPH-104 80 mg; Drug: Olokizumab 64 mg

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 372
• Phase: Phase 2; Phase 3

Contacts and Locations

Study Locations

• Russian Federation
  • Moscow, Russian Federation, 109386
    • Private healthcare institution "Clinical Hospital" Russian Railways-Medicine named after N. A. Semashko"
  • Moscow, Russian Federation, 111539
    • State Budget Healthcare Institution "City Clinical Hospital № 15 named after O.M. Filatov" of Moscow City Healthcare Department
  • Moscow, Russian Federation, 117997
    • Federal State Budgetary Institution "Federal Center for Cerebrovascular Pathology and Stroke" of the Ministry of Health of the Russian Federation
  • Moscow, Russian Federation, 119991
    • Federal State Autonomous Education Insitution of High Education the First Moscow State Medical University named after I.M. Sechenov of Ministry of Healthcare of Russian Federation (Sechenov University)
  • Moscow, Russian Federation, 119991
    • Federal State Autonomous Education Institution of High Education the First Moscow State Medical University named after I.M. Sechenov of Ministry of Healthcare of the Russian Federation (Sechenov University)
  • Moscow, Russian Federation, 121359
    • Federal State Budgetary Institution "Central Clinical Hospital with Polyclinic" of Administrative Directorate of the President of the Russian Federation
  • Moscow, Russian Federation, 121552
    • Federal State Budget Institution "National Medicine Research Center on Cardiology" By Ministry of Healthcare of Russian Federation
  • Moscow, Russian Federation, 123182
    • State Budget Institution of Healthcare "City Clinical Hospital #52", Moscow City Healthcare Department
  • Moscow, Russian Federation, 127206
    • State budgetary healthcare institution City Clinical Hospital named after S.I. Spasokukotsky Department of Health of the city of Moscow City Clinical Hospital No. 50
  • Moscow, Russian Federation, 129090
    • Moscow State Budget Institution of Healthcare "Scientific Research Institute of Emergency Medicine named after N.V. Sklifosovsky of Moscow Department of Healthcare"
  • Moscow, Russian Federation, 143442
    • АО "State Company "Medsi" based on Clinical Hospital №1"
  • Nizhniy Novgorod, Russian Federation, 603950
    • Federal State Budgetary Educational Institution of Higher Education "Volga Research Medical University" of the Ministry of Health of the Russian Federation
  • Saint Petersburg, Russian Federation, 197706
    • Saint-Petersburg State Budget Institution of Healthcare "City Hospital №40"
  • Saint-Petersburg, Russian Federation, 197341
    • Federal Budgetary State Healthcare Institution "National Medical Research Center named after B.A. Almazov"
  • Voronezh, Russian Federation, 394066
    • Budgetary Health Institution Voronezh Regional Clinical Hospital №1
  • Yaroslavl, Russian Federation, 150047
    • State Budget Healthcare Institution of Yaroslavl Region "Yaroslavl Region Clinical Hospital of War Veterans"

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Olokizumab 64 mg; Subject randomized to receive subcutaneous single injection of 0,4 ml solution of Olokizumab on Day 1, in addition to standard therapy	Drug: Olokizumab 64 mg; solution for subcutaneous administration 160 mg/mL, in the 2-mL glass vial (target volume 0,4 ml)
Experimental: RPH -104 80 mg; Subject randomized to receive subcutaneous single injection of 2 ml solution of RPH-104 on Day 1, in addition to standard therapy	Drug: RPH-104 80 mg; solution for subcutaneous administration 40 mg/mL, 2 mL in the 4-mL glass vial
Placebo Comparator: Placebo; Subject randomized to receive subcutaneous single injection of 2 ml solution of Placebo on Day 1, in addition to standard therapy	Drug: Placebo; Normal Saline (0.9% Sodium Chloride solution for Injection), in the market package

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Proportion of Responders in Each Treatment Group	Proportion of patients, responded to the study therapy, in each of the treatment groups. A responder is a patient who has not received tocilizumab or sarilumab and who has a clinical status improvement of ≥1 point on the 6-point COVID-19 scale (where 1 is the most favorable outcome and 6 is the most undesirable outcome) 15 days after the administration of the study drug: Not hospitalized, no activity limitations.; Not hospitalized, limited activity.; Hospitalized, not requiring supplemental oxygen.; Hospitalized, supplemental oxygen with independent breathing.; Hospitalized; mechanical ventilation (invasive/non-invasive) or Extracorporeal membrane oxygenation (ECMO).; Death.	Day 15

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change Over Time in the Clinical Status of Patients Using a 6-point Ordinal Scale	Changes of patients' clinical status on a 6 points ordinal scale (where 1 was the most favorable outcome and 6 was the most undesirable outcome) over time. The 6-point ordinal scale included the following categories: Not hospitalized, no activity limitations.; Not hospitalized, limited activity.; Hospitalized, not requiring supplemental oxygen.; Hospitalized, supplemental oxygen, with independent breathing.; Hospitalized, mechanical ventilation (invasive/non-invasive) or ECMO.; Death.	from Day 2 until Day 15, Day 29
The Proportion of Patients With an Improvement in Clinical Status by 2 or More Points on the 6-point Ordinal Scale During the Study With no Use of Tocilizumab or Sarilumab	The proportion of patients with an improvement in clinical status by 2 or more points on the 6-point ordinal scale (where 1 was the most favorable outcome and 6 was the most undesirable outcome) during the study with no use of tocilizumab or sarilumab. The 6-point ordinal scale included the following categories: Not hospitalized, no activity limitations.; Not hospitalized, limited activity.; Hospitalized, not requiring supplemental oxygen.; Hospitalized, supplemental oxygen, with independent breathing.; Hospitalized, mechanical ventilation (invasive/non-invasive) or ECMO.; Death.	Day 29
The Proportion of Patients Who Received Tocilizumab or Sarilumab for COVID-19 During the Study	The proportion of patients who received tocilizumab or sarilumab for COVID-19 during the study	from Day 2 until the Day 29
Mortality Rate During the Study	Mortality rate over the follow-up period of the study	from Day 1 until Day 29

Collaborators and Investigators

• Sponsor: R-Pharm International, LLC
• Collaborators: Data Management 365; K-Research, LLC

Study record dates

Study Major Dates

• Study Start (Actual): April 23, 2020
• Primary Completion (Actual): July 10, 2020
• Study Completion (Actual): July 24, 2020

Study Registration Dates

• First Submitted: May 6, 2020
• First Submitted That Met QC Criteria: May 6, 2020
• First Posted (Actual): May 8, 2020

Study Record Updates

• Last Update Posted (Actual): January 24, 2022
• Last Update Submitted That Met QC Criteria: January 21, 2022
• Last Verified: January 1, 2022

More Information

Terms related to this study

• Keywords: SARS-CoV-2; COVID-19; coronavirus; 2019-nCoV; Severe acute respiratory syndrome coronavirus 2; Respiratory disease; lung disease; 2019 novel coronavirus
• Additional Relevant MeSH Terms: Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Virus Diseases; Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Pneumonia, Viral; Pneumonia; Lung Diseases; Severe Acute Respiratory Syndrome; COVID-19
• Other Study ID Numbers: CL04041078

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No