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SILtuximab in Viral ARds (SILVAR) Study (SILVAR)

Primary Purpose

Acute Respiratory Distress Syndrome, Lung Diseases, Pneumonia

Status
Terminated
Phase
Phase 3
Locations
United States
Study Type
Interventional
Intervention
Siltuximab
Normal Saline
Sponsored by
EusaPharma (UK) Limited
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Acute Respiratory Distress Syndrome focused on measuring Siltuximab, ARDS

Eligibility Criteria

12 Years - 65 Years (Child, Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • Sparrow Clinical Research Institute
  • Atrium Health

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Other

Arm Label

Arm A

Arm B

Arm Description

Drug - Siltuximab

Comparator - Normal Saline

Outcomes

Primary Outcome Measures

28-day all-cause mortality
28-day all-cause mortality

Secondary Outcome Measures

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

Full Information

First Posted
October 10, 2020
Last Updated
April 15, 2021
Sponsor
EusaPharma (UK) Limited
Collaborators
Syneos Health
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1. Study Identification

Unique Protocol Identification Number
NCT04616586
Brief Title
SILtuximab in Viral ARds (SILVAR) Study
Acronym
SILVAR
Official Title
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)
Study Type
Interventional

2. Study Status

Record Verification Date
January 2021
Overall Recruitment Status
Terminated
Why Stopped
The REMAP-CAP and RECOVERY substudy results appear to support the survival benefit of tocilizumab in corticosteroid-treated or untreated patients with critically ill COVID-19-associated ARDS.
Study Start Date
November 13, 2020 (Actual)
Primary Completion Date
April 1, 2021 (Actual)
Study Completion Date
April 1, 2021 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
EusaPharma (UK) Limited
Collaborators
Syneos Health

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Acute Respiratory Distress Syndrome, Lung Diseases, Pneumonia, Respiratory Tract Infections, Respiratory Tract Disease
Keywords
Siltuximab, ARDS

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
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
Masking
ParticipantCare ProviderInvestigatorOutcomes 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.
Allocation
Randomized
Enrollment
555 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Arm A
Arm Type
Experimental
Arm Description
Drug - Siltuximab
Arm Title
Arm B
Arm Type
Other
Arm Description
Comparator - Normal Saline
Intervention Type
Drug
Intervention Name(s)
Siltuximab
Other Intervention Name(s)
Sylvant
Intervention Description
11 mg/kg IV administered over 1 hour
Intervention Type
Other
Intervention Name(s)
Normal Saline
Intervention Description
IV administered over 1 hour
Primary Outcome Measure Information:
Title
28-day all-cause mortality
Description
28-day all-cause mortality
Time Frame
Day 28
Secondary Outcome Measure Information:
Title
Time to 7-category ordinal scale of clinical status improvement (T7COSCSI)
Description
Time to 7-category ordinal scale of clinical status improvement (T7COSCSI)
Time Frame
Up to 60 days
Title
Ventilator-free days (VFDs) within 28 days
Description
Ventilator-free days (VFDs) within 28 days
Time Frame
Up to 28 days
Title
Organ failure-free days (OFFD)
Description
Organ failure-free days (OFFD)
Time Frame
Up to 60 days
Title
Intensive care unit length of stay (ICU LOS)
Description
Intensive care unit length of stay (ICU LOS)
Time Frame
Up to 60 days
Title
Hospital length of stay (HLOS)
Description
Hospital length of stay (HLOS)
Time Frame
Up to 60 days
Title
In-hospital all-cause mortality (IHACM)
Description
In-hospital all-cause mortality (IHACM)
Time Frame
Up to 60 days
Title
60-day all-cause mortality (60DACM)
Description
60-day all-cause mortality (60DACM)
Time Frame
Up to 60 days
Title
Time to oxygenation improvement (TOI)
Description
Time to oxygenation improvement (TOI)
Time Frame
Up to 60 days
Title
Duration of supplemental oxygen (DSO)
Description
Duration of supplemental oxygen (DSO)
Time Frame
Up to 60 days
Title
Chest radiographic improvement (CRI)
Description
Chest radiographic improvement (CRI)
Time Frame
Up to 60 days
Title
Time to National Early Warning Score 2 improvement (TNEWS2I)
Description
Time to National Early Warning Score 2 improvement (TNEWS2I)
Time Frame
Up to 60 days
Title
Treatment-emergent adverse events (TEAEs)
Description
Treatment-emergent adverse events (TEAEs)
Time Frame
Up to 60 days
Title
Plasma siltuximab concentrations (PSCs)
Description
Plasma siltuximab concentrations (PSCs)
Time Frame
Up to 60 days
Title
Anti-siltuximab antibodies (ASA)
Description
Anti-siltuximab antibodies (ASA)
Time Frame
Up to 60 days

10. Eligibility

Sex
All
Minimum Age & Unit of Time
12 Years
Maximum Age & Unit of Time
65 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Zainab Shahid, MD, Ph.D
Organizational Affiliation
Participating Site
Official's Role
Principal Investigator
Facility Information:
Facility Name
Sparrow Clinical Research Institute
City
Lansing
State/Province
Michigan
ZIP/Postal Code
48912
Country
United States
Facility Name
Atrium Health
City
Charlotte
State/Province
North Carolina
ZIP/Postal Code
28202
Country
United States

12. IPD Sharing Statement

Plan to Share IPD
No

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SILtuximab in Viral ARds (SILVAR) Study

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