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CompletedNCT04380519Updated Jan 24, 2022Results posted

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)

A Phase 2/3 interventional study of RPH-104 80 mg and Olokizumab 64 mg in COVID-19, sponsored by R-Pharm International, LLC. Completed at 16 sites in Russian Federation. Open to participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2022-01-24.

Sponsored by R-Pharm International, LLC · Phase 2/3, Interventional, and Treatment

Phase
Phase 2/3
Study type
Interventional
Enrollment
372
Allocation
Randomized
Ages
18 Years and older
Sex
All
01

Study summary

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.

Read the 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.

02

Conditions studied

  • COVID-19

Keywords

  • SARS-CoV-2
  • Severe acute respiratory syndrome coronavirus 2
  • 2019-nCoV
  • 2019 novel coronavirus
  • Respiratory disease
  • lung disease
  • COVID-19
  • coronavirus
03

In context

COVID-19

7,640 studies on the registry are indexed under COVID-19; 488 are open to participants now.

This study's enrollment of 372 is above the median of 100 across 4,099 interventional studies indexed under COVID-19.

Browse COVID-19 studies →

Lead sponsor

R-Pharm International, LLC is the lead sponsor of 17 studies on the registry; 4 are open to participants now.

Counted across the registry records on this site, refreshed daily.

04

Who can participate

Ages eligible
18 Years and older
Sexes eligible
All
Accepts healthy volunteers
No

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

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.
05

Study design

Phase
Phase 2 / Phase 3
Primary purpose
Treatment
Allocation
Randomized
Intervention model
Parallel assignment
Masking
Double (Participant, Investigator)
Enrollment
372 participants (actual)

Study arms

  • 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

  • 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

  • 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

Interventions

  • DrugRPH-104 80 mg

    solution for subcutaneous administration 40 mg/mL, 2 mL in the 4-mL glass vial

  • DrugOlokizumab 64 mg

    solution for subcutaneous administration 160 mg/mL, in the 2-mL glass vial (target volume 0,4 ml)

  • DrugPlacebo

    Normal Saline (0.9% Sodium Chloride solution for Injection), in the market package

06

What researchers measure

Primary outcomes

  1. 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: 1. Not hospitalized, no activity limitations. 2. Not hospitalized, limited activity. 3. Hospitalized, not requiring supplemental oxygen. 4. Hospitalized, supplemental oxygen with independent breathing. 5. Hospitalized; mechanical ventilation (invasive/non-invasive) or Extracorporeal membrane oxygenation (ECMO). 6. Death.

    Time frame: Day 15

Secondary outcomes

  1. 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: 1. Not hospitalized, no activity limitations. 2. Not hospitalized, limited activity. 3. Hospitalized, not requiring supplemental oxygen. 4. Hospitalized, supplemental oxygen, with independent breathing. 5. Hospitalized, mechanical ventilation (invasive/non-invasive) or ECMO. 6. Death.

    Time frame: from Day 2 until Day 15, Day 29

  2. 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: 1. Not hospitalized, no activity limitations. 2. Not hospitalized, limited activity. 3. Hospitalized, not requiring supplemental oxygen. 4. Hospitalized, supplemental oxygen, with independent breathing. 5. Hospitalized, mechanical ventilation (invasive/non-invasive) or ECMO. 6. Death.

    Time frame: Day 29

  3. 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

    Time frame: from Day 2 until the Day 29

  4. Mortality Rate During the Study

    Mortality rate over the follow-up period of the study

    Time frame: from Day 1 until Day 29

07

Results

Posted Jan 24, 2022

Participant flow

Enrollment was conducted at 16 clinical sites in Russian Federation. 381 subjects were screened and 372 subjects were enrolled (randomized). A total of 371 subjects were treated, and 336 subjects completed the study. A total of 372 subjects were analyzed for efficacy in the Intent-to-Treat (ITT) Population, 352 subjects in the modified ITT Population (mITT) and 371 subjects were analyzed for safety in the Safety Population.

Participant flow — Overall Study
MilestoneRPH -104 80 mgOlokizumab 64 mgPlacebo
Started124124124
Intent-to-treat (itt)124124124
Modified intent-to-treat (mitt)115119118
Safety population123124124
Completed106113117
Not completed18117
Withdrew: Withdrawal by subject401
Withdrew: Death1496
Withdrew: Adverse event010
Withdrew: Relatives' decision010

Outcome measures

PrimaryProportion 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: 1. Not hospitalized, no activity limitations. 2. Not hospitalized, limited activity. 3. Hospitalized, not requiring supplemental oxygen. 4. Hospitalized, supplemental oxygen with independent breathing. 5. Hospitalized; mechanical ventilation (invasive/non-invasive) or Extracorporeal membrane oxygenation (ECMO). 6. Death.

Time frame:
Day 15
Reported as:
Count of participants · Participants
Proportion of Responders in Each Treatment Group
ParticipantsRPH -104 80 mgOlokizumab 64 mgPlacebo
Proportion of Responders in Each Treatment Group889887
Statistical analysis
  • RPH -104 80 mg vs Placebo · Maximal Likelihood Estimator (MLE) model · p = 0.434 (Hochberg adjustment was applied for p-values) · Risk ratio (rr): 1.012
  • Olokizumab 64 mg vs Placebo · Maximal Likelihood Estimator (MLE) model · p = 0.073 (Hochberg adjustment was applied for p-values) · Risk ratio (rr): 1.125
SecondaryChange 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: 1. Not hospitalized, no activity limitations. 2. Not hospitalized, limited activity. 3. Hospitalized, not requiring supplemental oxygen. 4. Hospitalized, supplemental oxygen, with independent breathing. 5. Hospitalized, mechanical ventilation (invasive/non-invasive) or ECMO. 6. Death.

Time frame:
from Day 2 until Day 15, Day 29
Reported as:
Count of participants · Participants
Change Over Time in the Clinical Status of Patients Using a 6-point Ordinal Scale
ParticipantsRPH -104 80 mgOlokizumab 64 mgPlacebo
Day 15 — improvement889996
Day 15 — worsening (including deaths)1387
Day 15 — without change151117
Day 15 — no data864
Day 29 — improvement105113111
Day 29 — worsening (including deaths)1498
Day 29 — without change101
Day 29 — no data424
SecondaryThe 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: 1. Not hospitalized, no activity limitations. 2. Not hospitalized, limited activity. 3. Hospitalized, not requiring supplemental oxygen. 4. Hospitalized, supplemental oxygen, with independent breathing. 5. Hospitalized, mechanical ventilation (invasive/non-invasive) or ECMO. 6. Death.

Time frame:
Day 29
Reported as:
Count of participants · Participants
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
ParticipantsRPH -104 80 mgOlokizumab 64 mgPlacebo
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 Sarilumab9410394
Statistical analysis
  • RPH -104 80 mg vs Placebo · Maximal Likelihood Estimator (MLE) model · p = 0.393 (unadjusted) · Risk ratio (rr): 1.019
  • Olokizumab 64 mg vs Placebo · Maximal Likelihood Estimator (MLE) model · p = 0.061 (unadjusted) · Risk ratio (rr): 1.098
SecondaryThe 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

Time frame:
from Day 2 until the Day 29
Reported as:
Count of participants · Participants
The Proportion of Patients Who Received Tocilizumab or Sarilumab for COVID-19 During the Study
ParticipantsRPH -104 80 mgOlokizumab 64 mgPlacebo
The Proportion of Patients Who Received Tocilizumab or Sarilumab for COVID-19 During the Study10515
Statistical analysis
  • RPH -104 80 mg vs Placebo · Risk ratio (rr): 0.67 · 95% CI 0.31 to 1.44
  • Olokizumab 64 mg vs Placebo · Risk ratio (rr): 0.33 · 95% CI 0.12 to 0.89
  • RPH -104 80 mg vs Placebo · Odds ratio (or): 0.64 · 95% CI 0.28 to 1.49
  • Olokizumab 64 mg vs Placebo · Odds ratio (or): 0.31 · 95% CI 0.11 to 0.87
SecondaryMortality Rate During the Study

Mortality rate over the follow-up period of the study

Time frame:
from Day 1 until Day 29
Reported as:
Count of participants · Participants
Mortality Rate During the Study
ParticipantsRPH -104 80 mgOlokizumab 64 mgPlacebo
Mortality Rate During the Study1496
Statistical analysis
  • RPH -104 80 mg vs Placebo · Risk ratio (rr): 2.35 · 95% CI 0.93 to 5.92
  • Olokizumab 64 mg vs Placebo · Risk ratio (rr): 1.5 · 95% CI 0.55 to 4.09
  • RPH -104 80 mg vs Placebo · Odds ratio (or): 2.53 · 95% CI 0.94 to 6.81
  • Olokizumab 64 mg vs Placebo · Odds ratio (or): 1.54 · 95% CI 0.53 to 4.46

Adverse events

Collected over All Adverse Events (AEs), except serious ones, were recorded from the moment of the use of the IP. AEs recorded prior to the start of the study therapy, but after the patient was included in the study, were recorded in the electronic CRF Case report form (eCRF) as "Concomitant diseases". AEs were registered until the end of the follow-up period (day 29).. Non-serious events are listed at a 5% frequency threshold.

Adverse event summary by group
GroupDeathsSeriousOther
RPH -104 80 mg14/123 (11.4%)15/123 (12.2%)30/123 (24.4%)
Olokizumab 64 mg9/124 (7.3%)10/124 (8.1%)23/124 (18.5%)
Placebo6/124 (4.8%)8/124 (6.5%)35/124 (28.2%)
Most frequent serious events
Showing 10 of 15
Most frequent serious events
EventRPH -104 80 mgOlokizumab 64 mgPlacebo
SepsisInfections and infestations3/1232/1243/124
Pulmonary embolismRespiratory, thoracic and mediastinal disorders1/1233/1240/124
Cardiac failure acuteCardiac disorders2/1230/1240/124
Septic shockInfections and infestations2/1230/1241/124
Acute respiratory distress syndromeRespiratory, thoracic and mediastinal disorders2/1232/1241/124
Type 2 diabetes mellitusMetabolism and nutrition disorders0/1230/1242/124
Atrial fibrillationCardiac disorders1/1230/1240/124
COVID-19Infections and infestations1/1231/1241/124
Viral sepsisInfections and infestations1/1230/1240/124
Cerebral infarctionNervous system disorders1/1230/1240/124
Most frequent other events
Most frequent other events
EventRPH -104 80 mgOlokizumab 64 mgPlacebo
Alanine aminotransferase increasedInvestigations13/12311/12415/124
Aspartate aminotransferase increasedInvestigations12/1239/12412/124
Gamma-glutamyltransferase increasedInvestigations5/1233/1248/124

Baseline characteristics

Age, Continuous
Age, Continuous(years)RPH -104 80 mgOlokizumab 64 mgPlaceboTotal
Mean58.0 (28.0 to 92.0)59.6 (26.0 to 93.0)59.7 (29.0 to 86.0)59.1 (26.0 to 93.0)
Sex: Female, Male
Sex: Female, Male(Participants)RPH -104 80 mgOlokizumab 64 mgPlaceboTotal
Female615857176
Male636667196
Race/Ethnicity, Customized
Race/Ethnicity, Customized(Participants)RPH -104 80 mgOlokizumab 64 mgPlaceboTotal
White124123124371
Asian0101
Race/Ethnicity, Customized
Race/Ethnicity, Customized(Participants)RPH -104 80 mgOlokizumab 64 mgPlaceboTotal
Hispanic or Latino1001
Not Hispanic or Latino123123124370
Not reported0101
08

Study locations

16 sites
  • Private healthcare institution "Clinical Hospital" Russian Railways-Medicine named after N. A. Semashko"
    Moscow, 109386, Russian Federation
  • State Budget Healthcare Institution "City Clinical Hospital № 15 named after O.M. Filatov" of Moscow City Healthcare Department
    Moscow, 111539, Russian Federation
  • Federal State Budgetary Institution "Federal Center for Cerebrovascular Pathology and Stroke" of the Ministry of Health of the Russian Federation
    Moscow, 117997, Russian Federation
  • 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, 119991, Russian Federation
  • 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, 119991, Russian Federation
  • Federal State Budgetary Institution "Central Clinical Hospital with Polyclinic" of Administrative Directorate of the President of the Russian Federation
    Moscow, 121359, Russian Federation
  • Federal State Budget Institution "National Medicine Research Center on Cardiology" By Ministry of Healthcare of Russian Federation
    Moscow, 121552, Russian Federation
  • State Budget Institution of Healthcare "City Clinical Hospital #52", Moscow City Healthcare Department
    Moscow, 123182, Russian Federation
  • 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, 127206, Russian Federation
  • Moscow State Budget Institution of Healthcare "Scientific Research Institute of Emergency Medicine named after N.V. Sklifosovsky of Moscow Department of Healthcare"
    Moscow, 129090, Russian Federation
  • АО "State Company "Medsi" based on Clinical Hospital №1"
    Moscow, 143442, Russian Federation
  • Federal State Budgetary Educational Institution of Higher Education "Volga Research Medical University" of the Ministry of Health of the Russian Federation
    Nizhniy Novgorod, 603950, Russian Federation
  • Saint-Petersburg State Budget Institution of Healthcare "City Hospital №40"
    Saint Petersburg, 197706, Russian Federation
  • Federal Budgetary State Healthcare Institution "National Medical Research Center named after B.A. Almazov"
    Saint-Petersburg, 197341, Russian Federation
  • Budgetary Health Institution Voronezh Regional Clinical Hospital №1
    Voronezh, 394066, Russian Federation
  • State Budget Healthcare Institution of Yaroslavl Region "Yaroslavl Region Clinical Hospital of War Veterans"
    Yaroslavl, 150047, Russian Federation
09

References and documents

Study documents

  • Protocol and statistical analysis plan · Apr 26, 2020

Documents are hosted by the registry — open the source record to download them.

10

Updates

Tracking since Sep 25, 2026
No changes since tracking began. The registry record was last updated on Jan 24, 2022, before this site started recording changes on Sep 25, 2026. Its history is on ClinicalTrials.gov ↗
11

Registry details

Key details

Study ID
NCT04380519
Lead sponsor
R-Pharm International, LLC
Collaborators
Data Management 365, K-Research, LLC
Responsible party
Sponsor
First posted
May 8, 2020
Start date
Apr 23, 2020
Primary completion
Jul 10, 2020
Completion
Jul 24, 2020
Results posted
Jan 24, 2022
Last update
Jan 24, 2022

Study contacts

Mikhail Samsonov
study director · Chief Medical Officer, R-Pharm

Oversight

Data monitoring committee
Yes
FDA-regulated drug
No
FDA-regulated device
No
View the source record on ClinicalTrials.gov ↗

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