Acute Respiratory Distress Syndrome, Lung Diseases, Pneumonia, Respiratory Tract Disease, Respiratory Tract Infections
Conditions
Keywords
Siltuximab, ARDS
Brief summary
This study will evaluate the efficacy and safety of siltuximab compared with normal saline in combination with standard of care (SOC) in selected hospitalized patients with COVID-19 previously treated with corticosteroids or another respiratory virus infection associated with acute respiratory distress syndrome (ARDS) and elevated C-reactive protein (CRP) levels.
Detailed description
This is a prospective, multicenter, randomized (2:1), double-blind, parallel-arm, placebo-controlled, Phase 3 clinical trial of 1-3 doses of siltuximab 11 mg/kg IV over 1 hour plus SOC vs. matched-volume normal saline (NS) IV over 1 hour plus SOC in 555 patients with SARS CoV-2 previously treated with corticosteroids or another respiratory virus infection with elevated CRP levels who have developed serious respiratory complications. The randomization will be stratified by age (\<65, ≥65 years), respiratory virus infection (confirmed SARS-CoV-2, other), and MIV status (yes, no). Crossover between treatment arms will not be allowed. All patients will receive ARDS SOC following the official American Thoracic Society/European Society of Intensive Care Medicine/Society of Critical Care Medicine clinical practice guideline13 and/or the World Health Organization's (WHO's) clinical management of severe acute respiratory infection when COVID-19 disease is suspected (WHO Interim Guidance 202014 or other local guidance). Patients may continue receiving their corticosteroid (up to a cumulative maximum dexamethasone or equivalent dose of 60 mg \[except to treat treatment-emergent reactions or comorbid conditions\]) or antiviral therapy (except aminoquinoline compounds and convalescent plasma) at the same or lower doses if started at least 4 days (corticosteroid therapy) or at least 2 days (antiviral therapy) prior to randomization. Patients randomized to Arm A will additionally receive siltuximab 11 mg/kg IV administered over 1 hour, while patients randomized to Arm B will additionally receive IV NS administered over 1 hour, with opportunity to repeat their assigned study treatment once or twice at least 2 days apart on or after Day 3 as their clinical condition and/or laboratory testing dictate.
Interventions
DRUGSiltuximab
11 mg/kg IV administered over 1 hour
OTHERNormal Saline
IV administered over 1 hour
Sponsors
Syneos Health
RECORDATI GROUP
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
At all times, randomized study treatment assignment information will be kept confidential and will not be released to the patient, investigator, the study staff (except the pharmacist), or the Sponsor's Study Team until following the conclusion of the study, except as described below. At the initiation of the study, the study site will be instructed on procedures for breaking the blind. Blinding codes should be broken only in emergency situations for reasons of patient safety. If a patient has an AE that may be considered treatment-related, treatment for the AE should be administered as if the patient is receiving siltuximab. Whenever possible, the investigator should contact the Sponsor's Medical Monitor before breaking the blind. When the blind for a patient has been broken, the reason must be fully documented. The patient for whom the blind has been broken will not receive further doses of study treatment.
Intervention model description
This is a prospective, multicenter, randomized (2:1), double-blind, parallel-arm, placebo-controlled, Phase 3 clinical trial of 1-3 doses of siltuximab 11 mg/kg IV over 1 hour plus SOC vs. matched-volume normal saline (NS) IV over 1 hour plus SOC in 555 patients with SARS-CoV-2 previously treated with corticosteroids or another respiratory virus infection with elevated CRP levels who have developed serious respiratory complications
Eligibility
Sex/Gender
ALL
Age
12 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
* Positive microbiological evidence of SARS-CoV-2 or another respiratory virus infection (eg, other coronaviruses, respiratory syncytial virus, influenza virus) following institutional diagnostic standards * Clinical and radiological diagnosis of pulmonary infection requiring noninvasive or mechanical invasive ventilatory support plus administration of rising supplemental oxygen concentrations * Treatment of SARS-CoV-2-infected patients with dexamethasone (or equivalent) administered by mouth or intravenous (IV) injection * Diagnosis of ARDS (PaO2/FiO2 ≤200 with positive end-expiratory pressure ≥5 cmH2O) in accordance with Berlin 2012 criteria1 (measured on or after the fourth day after the start of corticosteroid therapy in those patients for whom it was prescribed) * Serum CRP level greater than upper limit of normal (measured on or after the third day after the start of corticosteroid therapy in those patients for whom it was prescribed) on 2 consecutive days * Age ≥12 years
Exclusion criteria
* Active bacterial or fungal infection, human immunodeficiency virus (HIV), HHV, Epstein-Barr virus, or other non-respiratory virus infection, or tuberculosis requiring initiation of anti-infective therapy * Prior treatment with an agent targeting the IL-6 signaling pathway * Current treatment in another therapeutic clinical trial (other than expanded remdesivir access protocol) * Start of new immunosuppressive therapy (including but not limited to corticosteroids and cytokine signaling pathway inhibitors) within 4 days prior to study entry (randomization); start of new antiviral treatment (including but not limited to nucleoside analogues, aminoquinoline compounds, and convalescent plasma) within 2 days prior to randomization; or received a live vaccine at any time prior to randomization, or plan to receive a live vaccine during the study
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 28-day all-cause mortality | Day 28 | 28-day all-cause mortality |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Anti-siltuximab antibodies (ASA) | Up to 60 days | Anti-siltuximab antibodies (ASA) |
| Time to 7-category ordinal scale of clinical status improvement (T7COSCSI) | Up to 60 days | Time to 7-category ordinal scale of clinical status improvement (T7COSCSI) |
| Ventilator-free days (VFDs) within 28 days | Up to 28 days | Ventilator-free days (VFDs) within 28 days |
| Organ failure-free days (OFFD) | Up to 60 days | Organ failure-free days (OFFD) |
| Intensive care unit length of stay (ICU LOS) | Up to 60 days | Intensive care unit length of stay (ICU LOS) |
| Hospital length of stay (HLOS) | Up to 60 days | Hospital length of stay (HLOS) |
| Plasma siltuximab concentrations (PSCs) | Up to 60 days | Plasma siltuximab concentrations (PSCs) |
| 60-day all-cause mortality (60DACM) | Up to 60 days | 60-day all-cause mortality (60DACM) |
| Time to oxygenation improvement (TOI) | Up to 60 days | Time to oxygenation improvement (TOI) |
| Duration of supplemental oxygen (DSO) | Up to 60 days | Duration of supplemental oxygen (DSO) |
| Chest radiographic improvement (CRI) | Up to 60 days | Chest radiographic improvement (CRI) |
| Time to National Early Warning Score 2 improvement (TNEWS2I) | Up to 60 days | Time to National Early Warning Score 2 improvement (TNEWS2I) |
| Treatment-emergent adverse events (TEAEs) | Up to 60 days | Treatment-emergent adverse events (TEAEs) |
| In-hospital all-cause mortality (IHACM) | Up to 60 days | In-hospital all-cause mortality (IHACM) |
Countries
United States
Outcome results
None listed