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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)

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ClinicalTrials.gov Identifier: NCT04380519
Recruitment Status : Recruiting
First Posted : May 8, 2020
Last Update Posted : May 8, 2020
Sponsor:
Collaborators:
Data Management 365 LLC
K-Research, LLC
Information provided by (Responsible Party):
R-Pharm ( R-Pharm International, LLC )

Brief Summary:
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

Condition or disease Intervention/treatment Phase
COVID-19 Biological: RPH-104 80 mg Drug: Olokizumab 64 mg Drug: Placebo Phase 2 Phase 3

Detailed 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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 372 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Official Title: 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)
Actual Study Start Date : April 23, 2020
Estimated Primary Completion Date : October 15, 2020
Estimated Study Completion Date : November 15, 2020

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
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
Biological: RPH-104 80 mg
solution for subcutaneous administration 40 mg/mL, 2 mL in the 4-mL glass vial

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)

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




Primary Outcome Measures :
  1. Proportion of patients, responded to the study therapy, in each of the treatment groups [ Time Frame: Day 15 ]
    Proportion of patients, responded to the study therapy, in each of the treatment groups. The patient can be considered as the therapy responder, in case tocilizumab or sarilumab were not administered and there is an improvement of a clinical status at least by 1 point on a 6-points COVID-19 scale, where 1 point means most favorable outcome, 6 points means most undesirable outcome.


Secondary Outcome Measures :
  1. Changes of patients' clinical status on a 6 points ordinal scale over time [ Time Frame: from Day 2 until Day 15, Day 29 ]
    Changes of patients' clinical status on a 6 points ordinal scale over time

  2. Mortality rate over the follow-up period [ Time Frame: from Day 1 until Day 29 ]
    Mortality rate over the follow-up period

  3. Improvement of the patient's clinical status by at least 2 points on a 6-point ordinal scale in the absence of tocilizumab or sarilumab administration. [ Time Frame: on screening and then from Day 1 until Day 29 ]
    Improvement of the patient's clinical status by at least 2 points on a 6-point ordinal scale in the absence of tocilizumab or sarilumab administration.

  4. Proportion of patients received tocilizumab or sarilumab due to COVID-19 [ Time Frame: from Day 1 until the Day 29 ]
    Proportion of patients received tocilizumab or sarilumab due to COVID-19


Other Outcome Measures:
  1. Proportion of patients having National Early Warning Score 2 of ≤ 4 maintained for 2 consecutive days [ Time Frame: from day 3 until day 15 ]
    Proportion of patients having National Early Warning Score 2 (NEWS2) of ≤ 4 maintained for 2 consecutive days

  2. Time to a NEWS2 of ≤ 2 maintained for two consecutive days [ Time Frame: from day 1 until day 15 ]
    Time to a NEWS2 of ≤ 2 maintained for two consecutive days

  3. Changes from baseline of cytokine storm surrogate markers: white blood counts, lymphocyte counts, neutrophils counts, C-Reactive protein (CRP), ferritin (if applicable), D-dimer (if applicable) [ Time Frame: Day 2, Day 3, Day5, Day 7, Day 15 ]
    Changes from baseline of cytokine storm surrogate markers: white blood counts, lymphocyte counts, neutrophils counts, CRP, ferritin (if applicable), D-dimer (if applicable)

  4. Mortality during an ICU stay, on days 7, 15, 29 of the study [ Time Frame: On Day 7, Day 15, Day 29 ]
    Mortality during an ICU stay, on days 7, 15, 29 of the study

  5. Time to increase of oxygen saturation SpO2 ≥ 94% n the absence of oxygen support maintained for two consecutive days [ Time Frame: from Day 2 until Day 15 ]
    Time to increase of oxygen saturation SpO2 ≥ 94% n the absence of oxygen support maintained for two consecutive days

  6. Changes of oxygenation index PaO2/FiO2 from baseline (if applicable) during hospitalization period [ Time Frame: On Day 1 and from Day 2 until Day 15 ]
    Changes of oxygenation index PaO2/FiO2 from baseline (if applicable) during hospitalization period

  7. Duration of ICU stay measured in days [ Time Frame: from Day 2 until Day 15 ]
    Duration of ICU stay measured in days

  8. Changes from baseline (if applicable) in severity of Acute Respiratory Distress Syndrome (ARDS) according to World Health Organization (WHO) criteria [ Time Frame: from Day 1 until Day 15 ]
    Changes from baseline (if applicable) in severity of ARDS according to WHO criteria

  9. Duration of mechanical ventilation and Extracorporeal Membrane Oxygenation (EMO) (if applicable) measured in days [ Time Frame: from Day 2 until Day 15 ]
    Duration of mechanical ventilation and EMO (if applicable) measured in days

  10. Duration of oxygen support (if applicable) measured in days [ Time Frame: from Day 1 until Day 15 ]
    Duration of oxygen support (if applicable) measured in days

  11. Proportion of patients having National Early Warning Score 2 of ≤ 2 maintained for 2 consecutive days [ Time Frame: from day 3 until day 15 ]
    Proportion of patients having National Early Warning Score 2 of ≤ 2 maintained for 2 consecutive days

  12. Time to a NEWS2 of ≤ 4 maintained for two consecutive days [ Time Frame: from day 1 until day 15 ]
    Time to a NEWS2 of ≤ 4 maintained for two consecutive days

  13. Time to improvement in severity of ARDS according to WHO criteria in one category changing from baseline (if applicable) [ Time Frame: On Day 1 and from Day 2 until Day 15 ]
    Time to improvement in severity of ARDS according to WHO criteria in one category changing from baseline (if applicable)

  14. Time to fever resolution i.e. setting of axillary body temperature <38 °C without antipyretics when measured for 2 consecutive days (if applicable) [ Time Frame: from day 1 until day 15 ]
    Time to fever resolution i.e. setting of axillary body temperature <38 °C without antipyretics when measured for 2 consecutive days (if applicable)

  15. Time to improvement of clinical status by 1 point on a 6-points COVID-19 scale [ Time Frame: from day 1 until day 29 ]
    Time to improvement of clinical status by 1 point on a 6-points COVID-19 scale

  16. Time to improvement of clinical status by 2 points on a 6-points COVID-19 scale [ Time Frame: from day 1 until day 29 ]
    Time to improvement of clinical status by 2 points on a 6-points COVID-19 scale

  17. Proportion of patients with the deterioration of clinical status by 1 point on a 6-points COVID-19 scale during the study [ Time Frame: from Day 1 until Day 29 ]
    Proportion of patients with the deterioration of clinical status by 1 point on a 6-points COVID-19 scale during the study

  18. Proportion of patients with the deterioration of clinical status by 1 point on a 6-points COVID-19 scale during the study, excluding the patients moved to the category 6, if applicable [ Time Frame: from Day 1 until Day 29 ]
    Proportion of patients with the deterioration of clinical status by 1 point on a 6-points COVID-19 scale during the study, excluding the patients moved to the category 6, if applicable

  19. Time to the deterioration of clinical status by 1 point on a 6-points COVID-19 scale during the study (if applicable) [ Time Frame: from Day 1 until Day 29 ]
    Time to the deterioration of clinical status by 1 point on a 6-points COVID-19 scale during the study (if applicable)



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years to 100 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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 α (TNFα) 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:

      1. high-dose glucocorticoids ( > 1mg/kg of prednisolone equivalent), oral and parental;
      2. 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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04380519


Locations
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Russian Federation
Federal State Budget Institution "National Medical Surgery Center named after N.I. Pirogov" of Ministry of Health of Russian Federation Not yet recruiting
Moscow, Russian Federation, 105203
Contact: Boris A. Teplykh    +79166166038    batru@mail.ru   
State Budget Healthcare Institution "City Clinical Hospital № 15 named after O.M. Filatov" of Moscow City Healthcare Department Not yet recruiting
Moscow, Russian Federation, 111539
Contact: Ivan G. Gordeev    +79122899213    cardio-15@yandex.ru   
Federal State Budgetary Institution "Federal Center for Cerebrovascular Pathology and Stroke" of the Ministry of Health of the Russian Federation Not yet recruiting
Moscow, Russian Federation, 117997
Contact: Mikhail A. Soldatov    +79151281583    soldatov1477@gmail.com   
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) Recruiting
Moscow, Russian Federation, 119991
Contact: Tatiana I. Ishina    +79265634639    ishin@newmail.ru   
Federal State Budget Institution "National Medicine Research Center on Cardiology" By Ministry of Healthcare of Russian Federation Recruiting
Moscow, Russian Federation, 121552
Contact: Marat V. Ezhov    +79104137499    marat_ezhov@mail.ru   
State Budget Institution of Healthcare "City Clinical Hospital #52", Moscow City Healthcare Department Recruiting
Moscow, Russian Federation, 123182
Contact: Daria S. Fomina    +79165971806    Daria_fomina@mail.ru   
Moscow State Budget Institution of Healthcare "Scientific Research Institute of Emergency Medicine named after N.V. Sklifosovsky of Moscow Department of Healthcare" Recruiting
Moscow, Russian Federation, 129090
Contact: Vladimir V. Kulabukhov    +79255068081    v.kulabukhov@gmail.com   
State Budget Healthcare Institution "City Clinical Hospital #40", Moscow City Healthcare Department, "Communarca" Division Not yet recruiting
Moscow, Russian Federation, 129301
Contact: Denis N. Protsenko    +79099013030    drprotsenko@me.com   
АО "State Company "Medsi" based on Clinical Hospital №1" Not yet recruiting
Moscow, Russian Federation, 143442
Contact: Anastasia S. Mochalova    +79264179316    denisovaas@mail.ru   
Saint Petersburg State Budget Institution of Healthcare "Clinical infectious diseases hospital named after S.P. Botkin" Not yet recruiting
Saint Petersburg, Russian Federation, 191167
Contact: Denis A. Gusev    +79219508025    gusevden-70@mail.ru   
Saint-Petersburg State Budget Institution of Healthcare "City Hospital №40" Recruiting
Saint Petersburg, Russian Federation, 197706
Contact: Alina A. Agafyina    +79215837808    a.agafina@mail.ru   
Sponsors and Collaborators
R-Pharm International, LLC
Data Management 365 LLC
K-Research, LLC
Investigators
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Study Director: Mikhail Samsonov Chief Medical Officer, R-Pharm
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Responsible Party: R-Pharm International, LLC
ClinicalTrials.gov Identifier: NCT04380519    
Other Study ID Numbers: CL04041078
First Posted: May 8, 2020    Key Record Dates
Last Update Posted: May 8, 2020
Last Verified: May 2020

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by R-Pharm ( R-Pharm International, LLC ):
SARS-CoV-2
Severe acute respiratory syndrome coronavirus 2
2019-nCoV
2019 novel coronavirus
Respiratory disease
lung disease
COVID-19
coronavirus
Additional relevant MeSH terms:
Layout table for MeSH terms
Coronavirus Infections
Severe Acute Respiratory Syndrome
Coronaviridae Infections
Nidovirales Infections
RNA Virus Infections
Virus Diseases
Respiratory Tract Infections
Respiratory Tract Diseases