COVID-19
Conditions
Keywords
SARS-CoV-2, Severe acute respiratory syndrome coronavirus 2, 2019-nCoV, 2019 novel coronavirus, Respiratory disease, lung disease, COVID-19, coronavirus
Brief 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.
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.
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
Sponsors
Data Management 365
K-Research, LLC
R-Pharm International, LLC
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
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
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Proportion of Responders in Each Treatment Group | Day 15 | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change Over Time in the Clinical Status of Patients Using a 6-point Ordinal Scale | from Day 2 until Day 15, Day 29 | 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. |
| 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 | Day 29 | 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. |
| The Proportion of Patients Who Received Tocilizumab or Sarilumab for COVID-19 During the Study | from Day 2 until the Day 29 | The proportion of patients who received tocilizumab or sarilumab for COVID-19 during the study |
| Mortality Rate During the Study | from Day 1 until Day 29 | Mortality rate over the follow-up period of the study |
Countries
Russia
Participant flow
Recruitment details
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.
Participants by arm
| Arm | Count |
|---|---|
| RPH -104 80 mg Subcutaneous single injection of RPH-104 80 mg (2 ml 40 mg/mL solution) on Day 1, in addition to standard therapy. | 124 |
| Olokizumab 64 mg Subcutaneous single injection of Olokizumab 64 mg (0,4 ml 160 mg/mL solution) on Day 1, in addition to standard therapy. | 124 |
| Placebo Subcutaneous single injection of 2 ml solution of Placebo (Normal Saline) on Day 1, in addition to standard therapy. | 124 |
| Total | 372 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 1 | 0 |
| Overall Study | Death | 14 | 9 | 6 |
| Overall Study | relatives' decision | 0 | 1 | 0 |
| Overall Study | Withdrawal by Subject | 4 | 0 | 1 |
Baseline characteristics
| Characteristic | RPH -104 80 mg | Olokizumab 64 mg | Placebo | Total |
|---|---|---|---|---|
| Age, Continuous | 58.0 years | 59.6 years | 59.7 years | 59.1 years |
| Race/Ethnicity, Customized Asian | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Hispanic or Latino | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Not Hispanic or Latino | 123 Participants | 123 Participants | 124 Participants | 370 Participants |
| Race/Ethnicity, Customized Not reported | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized White | 124 Participants | 123 Participants | 124 Participants | 371 Participants |
| Sex: Female, Male Female | 61 Participants | 58 Participants | 57 Participants | 176 Participants |
| Sex: Female, Male Male | 63 Participants | 66 Participants | 67 Participants | 196 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 14 / 123 | 9 / 124 | 6 / 124 |
| other Total, other adverse events | 30 / 123 | 23 / 124 | 35 / 124 |
| serious Total, serious adverse events | 15 / 123 | 10 / 124 | 8 / 124 |
Outcome results
Primary
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
Population: The intent-to-treat (ITT) population included all randomized patients.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| RPH -104 80 mg | Proportion of Responders in Each Treatment Group | 88 Participants |
| Olokizumab 64 mg | Proportion of Responders in Each Treatment Group | 98 Participants |
| Placebo | Proportion of Responders in Each Treatment Group | 87 Participants |
p-value: 0.434Maximal Likelihood Estimator (MLE) model
p-value: 0.073Maximal Likelihood Estimator (MLE) model
Secondary
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
Population: The ITT population was the primary analysis population.
| Arm | Measure | Group | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|---|
| RPH -104 80 mg | Change Over Time in the Clinical Status of Patients Using a 6-point Ordinal Scale | Day 15 | improvement | 88 Participants |
| RPH -104 80 mg | Change Over Time in the Clinical Status of Patients Using a 6-point Ordinal Scale | Day 15 | worsening (including deaths) | 13 Participants |
| RPH -104 80 mg | Change Over Time in the Clinical Status of Patients Using a 6-point Ordinal Scale | Day 15 | without change | 15 Participants |
| RPH -104 80 mg | Change Over Time in the Clinical Status of Patients Using a 6-point Ordinal Scale | Day 15 | no data | 8 Participants |
| RPH -104 80 mg | Change Over Time in the Clinical Status of Patients Using a 6-point Ordinal Scale | Day 29 | improvement | 105 Participants |
| RPH -104 80 mg | Change Over Time in the Clinical Status of Patients Using a 6-point Ordinal Scale | Day 29 | worsening (including deaths) | 14 Participants |
| RPH -104 80 mg | Change Over Time in the Clinical Status of Patients Using a 6-point Ordinal Scale | Day 29 | without change | 1 Participants |
| RPH -104 80 mg | Change Over Time in the Clinical Status of Patients Using a 6-point Ordinal Scale | Day 29 | no data | 4 Participants |
| Olokizumab 64 mg | Change Over Time in the Clinical Status of Patients Using a 6-point Ordinal Scale | Day 15 | without change | 11 Participants |
| Olokizumab 64 mg | Change Over Time in the Clinical Status of Patients Using a 6-point Ordinal Scale | Day 29 | without change | 0 Participants |
| Olokizumab 64 mg | Change Over Time in the Clinical Status of Patients Using a 6-point Ordinal Scale | Day 15 | no data | 6 Participants |
| Olokizumab 64 mg | Change Over Time in the Clinical Status of Patients Using a 6-point Ordinal Scale | Day 29 | improvement | 113 Participants |
| Olokizumab 64 mg | Change Over Time in the Clinical Status of Patients Using a 6-point Ordinal Scale | Day 29 | worsening (including deaths) | 9 Participants |
| Olokizumab 64 mg | Change Over Time in the Clinical Status of Patients Using a 6-point Ordinal Scale | Day 15 | improvement | 99 Participants |
| Olokizumab 64 mg | Change Over Time in the Clinical Status of Patients Using a 6-point Ordinal Scale | Day 15 | worsening (including deaths) | 8 Participants |
| Olokizumab 64 mg | Change Over Time in the Clinical Status of Patients Using a 6-point Ordinal Scale | Day 29 | no data | 2 Participants |
| Placebo | Change Over Time in the Clinical Status of Patients Using a 6-point Ordinal Scale | Day 15 | without change | 17 Participants |
| Placebo | Change Over Time in the Clinical Status of Patients Using a 6-point Ordinal Scale | Day 15 | worsening (including deaths) | 7 Participants |
| Placebo | Change Over Time in the Clinical Status of Patients Using a 6-point Ordinal Scale | Day 15 | improvement | 96 Participants |
| Placebo | Change Over Time in the Clinical Status of Patients Using a 6-point Ordinal Scale | Day 15 | no data | 4 Participants |
| Placebo | Change Over Time in the Clinical Status of Patients Using a 6-point Ordinal Scale | Day 29 | without change | 1 Participants |
| Placebo | Change Over Time in the Clinical Status of Patients Using a 6-point Ordinal Scale | Day 29 | worsening (including deaths) | 8 Participants |
| Placebo | Change Over Time in the Clinical Status of Patients Using a 6-point Ordinal Scale | Day 29 | improvement | 111 Participants |
| Placebo | Change Over Time in the Clinical Status of Patients Using a 6-point Ordinal Scale | Day 29 | no data | 4 Participants |
Secondary
Mortality Rate During the Study
Mortality rate over the follow-up period of the study
Time frame: from Day 1 until Day 29
Population: The safety population included all patients who received the IP (371 patients: 124 patients in the OKZ group, 123/124 (99.2%) patients in the RPH-104 group (1 patient did not received the IP) and 124 patients in the Placebo group).
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| RPH -104 80 mg | Mortality Rate During the Study | 14 Participants |
| Olokizumab 64 mg | Mortality Rate During the Study | 9 Participants |
| Placebo | Mortality Rate During the Study | 6 Participants |
95% CI: [0.93, 5.92]
95% CI: [0.55, 4.09]
95% CI: [0.94, 6.81]
95% CI: [0.53, 4.46]
Secondary
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
Population: The ITT population was the primary analysis population.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| RPH -104 80 mg | The Proportion of Patients Who Received Tocilizumab or Sarilumab for COVID-19 During the Study | 10 Participants |
| Olokizumab 64 mg | The Proportion of Patients Who Received Tocilizumab or Sarilumab for COVID-19 During the Study | 5 Participants |
| Placebo | The Proportion of Patients Who Received Tocilizumab or Sarilumab for COVID-19 During the Study | 15 Participants |
95% CI: [0.31, 1.44]
95% CI: [0.12, 0.89]
95% CI: [0.28, 1.49]
95% CI: [0.11, 0.87]
Secondary
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
Population: The ITT population was the primary analysis population.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| RPH -104 80 mg | 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 | 94 Participants |
| Olokizumab 64 mg | 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 | 103 Participants |
| Placebo | 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 | 94 Participants |
p-value: 0.393Maximal Likelihood Estimator (MLE) model
p-value: 0.061Maximal Likelihood Estimator (MLE) model