SILtuximab in Viral ARds (SILVAR) Study (SILVAR)

A Study Comparing the Efficacy and Safety of Standard of Care With or Without Siltuximab in Selected Hospitalized Patients With Viral Acute Respiratory Distress Syndrome (SILVAR)

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.

Study Overview

• Status: Terminated
• Conditions: Respiratory Tract Infections; Pneumonia; Lung Diseases; Acute Respiratory Distress Syndrome; Respiratory Tract Disease
• Intervention / Treatment: Drug: Siltuximab; Other: Normal Saline

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.

• Study Type: Interventional
• Enrollment (Actual): 555
• Phase: Phase 3

Contacts and Locations

Study Locations

• United States
  • Michigan
    • Lansing, Michigan, United States, 48912
      • Sparrow Clinical Research Institute
  • North Carolina
    • Charlotte, North Carolina, United States, 28202
      • Atrium Health

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 12 years to 65 years (ADULT, OLDER_ADULT, CHILD)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: QUADRUPLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Arm A; Drug - Siltuximab	Drug: Siltuximab; 11 mg/kg IV administered over 1 hour; Other Names: Sylvant
OTHER: Arm B; Comparator - Normal Saline	Other: Normal Saline; IV administered over 1 hour

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
28-day all-cause mortality	28-day all-cause mortality	Day 28

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time to 7-category ordinal scale of clinical status improvement (T7COSCSI)	Time to 7-category ordinal scale of clinical status improvement (T7COSCSI)	Up to 60 days
Ventilator-free days (VFDs) within 28 days	Ventilator-free days (VFDs) within 28 days	Up to 28 days
Organ failure-free days (OFFD)	Organ failure-free days (OFFD)	Up to 60 days
Intensive care unit length of stay (ICU LOS)	Intensive care unit length of stay (ICU LOS)	Up to 60 days
Hospital length of stay (HLOS)	Hospital length of stay (HLOS)	Up to 60 days
In-hospital all-cause mortality (IHACM)	In-hospital all-cause mortality (IHACM)	Up to 60 days
60-day all-cause mortality (60DACM)	60-day all-cause mortality (60DACM)	Up to 60 days
Time to oxygenation improvement (TOI)	Time to oxygenation improvement (TOI)	Up to 60 days
Duration of supplemental oxygen (DSO)	Duration of supplemental oxygen (DSO)	Up to 60 days
Chest radiographic improvement (CRI)	Chest radiographic improvement (CRI)	Up to 60 days
Time to National Early Warning Score 2 improvement (TNEWS2I)	Time to National Early Warning Score 2 improvement (TNEWS2I)	Up to 60 days
Treatment-emergent adverse events (TEAEs)	Treatment-emergent adverse events (TEAEs)	Up to 60 days
Plasma siltuximab concentrations (PSCs)	Plasma siltuximab concentrations (PSCs)	Up to 60 days
Anti-siltuximab antibodies (ASA)	Anti-siltuximab antibodies (ASA)	Up to 60 days

Collaborators and Investigators

• Sponsor: EusaPharma (UK) Limited
• Collaborators: Syneos Health
• Investigators: Principal Investigator: Zainab Shahid, MD, Ph.D, Participating site

Study record dates

Study Major Dates

• Study Start (ACTUAL): November 13, 2020
• Primary Completion (ACTUAL): April 1, 2021
• Study Completion (ACTUAL): April 1, 2021

Study Registration Dates

• First Submitted: October 10, 2020
• First Submitted That Met QC Criteria: October 29, 2020
• First Posted (ACTUAL): November 5, 2020

Study Record Updates

• Last Update Posted (ACTUAL): April 19, 2021
• Last Update Submitted That Met QC Criteria: April 15, 2021
• Last Verified: January 1, 2021

More Information

Terms related to this study

• Keywords: ARDS; Siltuximab
• Additional Relevant MeSH Terms: Pathologic Processes; Infections; Respiration Disorders; Disease; Infant, Newborn, Diseases; Lung Injury; Infant, Premature, Diseases; Syndrome; Lung Diseases; Respiratory Tract Infections; Respiratory Distress Syndrome; Respiratory Distress Syndrome, Newborn; Acute Lung Injury; Respiratory Tract Diseases; Antineoplastic Agents; Siltuximab
• Other Study ID Numbers: EUSA SYL 0004

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

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