Study of the Efficacy and Safety of a Single Administration of Olokizumab vs. Placebo in Addition to Standard Treatment in Patients With Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Infection (COVID-19).

A Multicenter, Randomized, Double-blind, Adaptive, Placebo-controlled Study of the Efficacy and Safety of a Single Administration of Olokizumab vs. Placebo in Addition to Standard Treatment in Patients With Severe SARS-CoV-2 Infection (COVID-19)

The primary objective of the study is to evaluate the efficacy of a single dose of OKZ (64 mg) vs placebo in addition to standard therapy in patients with severe SARS-CoV-2 infection (COVID-19) at Day 29.

Study Overview

• Status: Withdrawn
• Conditions: COVID-19
• Intervention / Treatment: Drug: Olokizumab 64 mg; Drug: Placebo

Detailed Description

1. Pilot phase: the first 100 patients will be randomized in two groups to receive OKZ or placebo (50 patients per group). Early futility analysis will be performed based on the results obtained in the pilot period after 100th patient completed Visit 29. Enrollment will be paused after randomization of 100th patient, then interim analysis will be performed when all 100 patients complete Visit Day 29 or discontinue the study.Based on results of the pilot phase analysis the study could be stopped.
2. Pivotal phase: inclusion of patients until targeted sample size is reached and performing final safety and efficacy analysis.

Maximum expected study duration for each patient is 62 days, including 2 days of screening, 1 day of study drug administration, and 59 days of follow-up.

The study will include following periods:

1. Screening period lasting up to 48 hours prior to Day 1. After signing the informed consent by the patient or the legally acceptable representative or when prior consent of the patient is not possible, and the subject's legally acceptable representative is not available, after obtaining documented approval/favorable opinion for individual cases by the Institutional Review Board / Independent Ethic Committee (IRB/IEC), investigator will assess the subject's eligibility for the study.

2. Treatment period lasting from the beginning of Day 1 visit to 23:59 of the Day 1.

   Eligible patients will be randomized to one of two treatment groups to receive a single subcutaneous injection - OKZ 64 mg or placebo in addition to standard COVID-19 therapy according to institutional guidelines;

3. Follow-up period lasting from 00:00 of the Day 2 to 23:59 of the Day 60. If the patient is discharged earlier than Day 15, at Days 15 and 29 5-point clinical status scale will be assessed at the study site visit or by phone interview. If the patient is discharged after Day 15, but earlier than Day 29, at Day 29 5-point clinical status scale will be assessed at the study site visit or by phone interview. The end of study is Day 60, when 5-point clinical status scale will be assessed by phone interview.

Up to 376 randomized patients (full sample size) will be included in the study according to preliminary estimation.

• Study Type: Interventional
• Phase: Phase 2; Phase 3

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 98 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• COVID-19 diagnosis (confirmation of the presence of SARS-CoV-2 virus by rt-PCR) OR sample collection for SARS-CoV-2 virus rt-PCR if the results of SARS-CoV-2 virus rt-PCR are not available yet.
• Dated informed consent for participation in this study signed by the patient, or by the legally acceptable representative or when prior consent of the patient is not possible, and the subject's legally acceptable representative is not available, documented approval / favorable opinion by the IRB/IEC.
• SpO2 ≤93% (room air) or respiratory rate greater than 30/min (room air) or oxygenation index PaO2/FiO2 ≤300 mmHg (or SpO2/FiO2 ≤315 in the case PaO2/FiO2 assessment is not available (supplementary oxygen)
• Computed tomography findings: features consistent with bilateral COVID-19 viral pneumonia and no alternative explanation for these findings.

Exclusion Criteria:

• Presence of any of the following laboratory abnormalities:

absolute neutrophil counts <0,5 х 10^9/L white blood cell count < 2 х 10^9/L, platelet count < 50 х 10^9/L, Alanine aminotransferase (АLT) and/or Aspartate aminotransferase (AST) ≥3,0 х Upper Limit of Normal (ULN)

• Kidney injury with creatinine clearance <30 mL/min.
• Hypersensitivity to OKZ, and/or its components.
• Septic shock (need for vasopressors to maintain mean arterial pressure ≥ 65 mm Hg and lactate ≥2 mmol / L in the absence of hypovolemia).
• Estimated survival of less than 24 hours regardless of treatment.
• History of perforation of the gastrointestinal tract, history of diverticulitis.
• Recent (less than 5 half-lives), current or planned during the current study period use of immunosuppressive drugs:
• biologics (except OKZ) with immunosuppressive effect, including, but not limited to: Interleukin-1 (IL-1) inhibitors (anakinra, rilonacept, canakinumab), IL-6 inhibitors (tocilizumab, sarilumab, siltuximab, etc.), IL-17A inhibitors (seсukinumab, etc.), Tumor Necrosis Factor-alpha (TNF-alpha) inhibitors (infliximab, adalimumab, etanercept, etc.), anti-B-cells therapy, etc.;.

• other immunosuppressive drugs (excluding methotrexate in dose up to 25 mg/week), including but not limited to:

  1. Glucocorticoids in high doses (> 1 mg / kg equivalent of methylprednisolone) orally and parenterally;
  2. JAK inhibitors; etc.
• Concurrent participation in another clinical trial during 30 days before screening.
• Pregnancy or lactation.
• A history of active tuberculosis, or active tuberculosis suspected by the Investigator.
• Administration of plasma from COVID-19 reconvalescent donors for 4 weeks prior to the patient's inclusion in the study and/or planned administration during the study
• Patients who deteriorated into Category 4 of the 5-point clinical status scale within more than the last 24 hours.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

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
Placebo Comparator: Placebo; Subject randomized to receive subcutaneous single injection of 0,4 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
Percentage of subjects achieving a change in their clinical status defined as improvement for at least 2 categories of the 5-points clinical status scale relative to baseline or in the "Not hospitalized" category	Difference between OKZ and placebo groups in the percentage of subjects with an improvement of at least 2 categories of the 5-points clinical status scale relative to baseline or in the "Not hospitalized" category. The points of the scale are: 1. Not hospitalized; 2.Hospitalized, not requiring supplemental oxygen; 3.Hospitalized, supplemental oxygen, spontaneous breathing;4. Hospitalized, mechanical ventilation (invasive/non-invasive) or extracorporeal membrane oxygenation (ECMO); 5. Death	at Day 29

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Subjects' clinical status distribution based on 5-point clinical status scale during the study	Subjects' clinical status distribution based on 5-point clinical status scale during the study	from Day 2 tо Day 15, Day 29, Day 60
28-day case fatality rates	28-day case fatality rates	from Day 1 to Day 29

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Case fatality rates during the intensive care unit (ICU) stay, at Days 7, 15, and 60	Case fatality rates during the intensive care unit (ICU) stay at Days 7, 15, and 60	from Day 1 to Day 60
Duration of oxygen support	Duration of oxygen support (if applicable)	From Day 1 to Day 60
The time period until SpO2 ≥ 94% at ambient air during 2 consequence days is reached	The time period until SpO2 ≥ 94% at ambient air during 2 consequence days is reached	from Day 2 to Day 60
Changes of oxygenation index PaO2/FiO2 from baseline	Changes of oxygenation index PaO2/FiO2 from baseline (if applicable)	from Day 2 to Day 60
Duration of oxygen support (if applicable)	Duration of oxygen support (if applicable), in days	from Day 1 to Day 60
Duration of mechanical ventilation and/or ECMO (if applicable)	Duration of mechanical ventilation and/or ECMO (if applicable), in days	from Day 1 to Day 60
Duration of ICU stay (if applicable)	Duration of ICU stay (if applicable)	from Day 1 to Day 60
Changes from baseline of COVID-19 cytokine storm surrogate marker: white blood count	Changes from baseline of COVID-19 cytokine storm surrogate marker: white blood count	from Day 2 and until the end of hospitalization, Day 29 as a maximum
Changes from baseline of COVID-19 cytokine storm surrogate marker: lymphocyte count	Changes from baseline of COVID-19 cytokine storm surrogate marker: lymphocyte counts	from Day 2 and until the end of hospitalization, Day 29 as a maximum
Changes from baseline of COVID-19 cytokine storm surrogate marker: neutrophils count	Changes from baseline of COVID-19 cytokine storm surrogate marker: neutrophils count	from Day 2 and until the end of hospitalization, Day 29 as a maximum
Changes from baseline of COVID-19 cytokine storm surrogate marker: C-reactive protein (CRP)	Changes from baseline of COVID-19 cytokine storm surrogate marker: C-reactive protein (CRP)	from Day 2 and until the end of hospitalization, Day 29 as a maximum
Changes from baseline of COVID-19 cytokine storm surrogate marker: ferritin	Changes from baseline of COVID-19 cytokine storm surrogate marker: ferritin	from Day 2 and until the end of hospitalization, Day 29 as a maximum
Changes from baseline of COVID-19 cytokine storm surrogate marker:D-dimer	Changes from baseline of COVID-19 cytokine storm surrogate marker:D-dimer	from Day 2 and until the end of hospitalization, Day 29 as a maximum
Changes from baseline of COVID-19 cytokine storm surrogate marker:platelets	Changes from baseline of COVID-19 cytokine storm surrogate marker:platelets	from Day 2 and until the end of hospitalization, Day 29 as a maximum
Changes from baseline of COVID-19 cytokine storm surrogate marker: triglycerides	Changes from baseline of COVID-19 cytokine storm surrogate marker: triglycerides	from Day 2 and until the end of hospitalization, Day 29 as a maximum
The time period until National Early Warning Score 2 (NEWS2) ≤ 2 during 2 consequent days is reached	The time period until National Early Warning Score 2 (NEWS2) ≤ 2 during 2 consequent days is reached	from Day 1 and until the end of hospitalization, Day 29 as a maximum
The time period until National Early Warning Score 2 (NEWS2) ≤ 4 during 2 consequent days is reached	The time period until National Early Warning Score 2 (NEWS2) ≤ 4 during 2 consequent days is reached	from Day 1 and until the end of hospitalization, Day 29 as a maximum

Collaborators and Investigators

• Sponsor: R-Pharm
• Collaborators: Covance; Cromos Pharma LLC

Study record dates

Study Major Dates

• Study Start (Anticipated): June 30, 2020
• Primary Completion (Anticipated): November 16, 2020
• Study Completion (Anticipated): January 29, 2021

Study Registration Dates

• First Submitted: June 25, 2020
• First Submitted That Met QC Criteria: June 26, 2020
• First Posted (Actual): June 30, 2020

Study Record Updates

• Last Update Posted (Actual): November 8, 2021
• Last Update Submitted That Met QC Criteria: October 29, 2021
• Last Verified: October 1, 2021

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: CL04041080

Drug and device information, study documents

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