Early Treatment of Cytokine Storm Syndrome in Covid-19

• ClinicalTrials.gov Identifier: NCT04362111
• Recruitment Status: Active, not recruiting
• First Posted: April 24, 2020
• Last Update Posted: January 26, 2023
• Sponsor: University of Alabama at Birmingham
• Information provided by (Responsible Party): W Winn Chatham, University of Alabama at Birmingham

Tracking Information

• First Submitted Date: April 21, 2020
• First Posted Date: April 24, 2020
• Last Update Posted Date: January 26, 2023
• Actual Study Start Date: July 29, 2020
• Actual Primary Completion Date: December 31, 2021 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: September 8, 2020)

Percentage of patients discharged from the hospital alive and without the need for mechanical ventilation. [ Time Frame: Variable up to Day 28 ]

Percentage of subjects discharged from hospital without the need for intubation and mechanical ventilation

Original Primary Outcome Measures (submitted: April 23, 2020)

No increase in oxygen requirement and no increase in respiratory support measures [ Time Frame: 48 hours ]

Supplemental oxygen requirement to maintain oxygen saturation >90% stable or decreased without escalation of respiratory measures (addition of CPAP, initiation of mechanical ventilation)

Current Secondary Outcome Measures (submitted: January 23, 2023)

• Percentage of subjects with 25% change (decrease) in cytokine storm markers at 48 hours [ Time Frame: 48 hours ]
  25% change (decrease) in noted baseline elevations of serum ferritin, LDH, CRP, and d-dimer.
• Percentage of subjects without increase in oxygen requirement and no increase in oxygen delivery/respiratory support measures after 48 hours. [ Time Frame: Day 2 (48 hours)-Day 10 (240 hours) ]
  Supplemental oxygen requirement to maintain oxygen saturation >90% stable or decreased without escalation of respiratory support measures (addition of CPAP, initiation of mechanical ventilation)
• Average time in days to achieve sustained ≥93% oxygen saturation without oxygen/respiratory support [ Time Frame: 0-10 days ]
  Time from initial dosing of IP to achievement of ≥93% oxygen saturation on room air for 24 hours
• Percentage of subjects with resolution of laboratory markers of Cytokine Storm syndrome [ Time Frame: Day 10 ]
  Normalization or ≥ 75% improvement by Day 10 (120 hours) in each of the following laboratory CSS attributes elevated beyond the normal range at randomization: ferritin, fibrinogen, AST, ALT, leucopenia, thrombocytopenia, d-dimer, CRP, triglycerides, sCD25.
• Percentage of subjects who develop bacterial or fungal or non-Covid-19 viral infection [ Time Frame: Day 0-28 ]
  No increased prevalence of bacterial or fungal or viral infection through the time of hospital discharge until Day 28.

Original Secondary Outcome Measures (submitted: April 23, 2020)

• Improvement in Cytokine Storm markers [ Time Frame: 72 hours ]
  25% decrease in noted baseline elevations of serum ferritin, LDH, CRP, and d-dimer.
• No requirement for mechanical ventilation [ Time Frame: Day 5 (120 hours) ]
  Subjects discharged from hospital without the need for mechanical ventilation

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Early Treatment of Cytokine Storm Syndrome in Covid-19
• Official Title: Early Treatment of Cytokine Storm Syndrome in Covid-19
• Brief Summary: This proposal addresses the problem of preventing the very high mortality and morbidity associated with the development of Cytokine Storm Syndrome (CSS) associated respiratory failure in Covid-19 infection.
• Detailed Description: The first aim of this project is to determine whether rapidly assayed early clinical laboratory markers of CSS (eCSS: leucopenia, lymphopenia, and elevated ferritin, d-dimer, LDH, CRP, and AST/ALT) in patients admitted to the hospital with respiratory compromise in the setting of Covid-19 infection can accurately identify patients with CSS as defined by validated CSS case definitions (H-Score, aHLH-2004). Confirmation of eCSS predictive of evolving CSS will identify patients at risk for rapid deterioration of lung function and inform early initiation of treatment for CSS. Genotyping studies will also be performed on patients with confirmed CSS to determine whether perforin pathway mutations commonly present in CSS associated with other disorders are present. The second aim is to determine whether early treatment with rhIL-1Ra (anakinra) in patients admitted to the hospital with markers of CSS improves or prevents deterioration of respiratory dysfunction and prevents the development of respiratory failure requiring mechanical ventilation.
• Study Type: Interventional
• Study Phase: Phase 3

Study Design

Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:

Two parallel treatment arms

Masking: Triple (Participant, Care Provider, Investigator)
Masking Description:

Investigator, care provider, and participant blinded

Primary Purpose: Treatment

Condition

• Cytokine Storm
• COVID-19

Intervention

• Drug: Anakinra
  The active treatment group will receive anakinra 100 mg subcutaneously every 6-12 hours for a period of 10 days
  Other Name: recombinant human IL-ra (rhIL-1ra)
• Drug: Normal saline
  The control group will receive normal saline placebo subcutaneously every 6-12 hours for period of 10 days
  Other Name: NS

Study Arms

• Experimental: Anakinra Group
  The active treatment group will receive anakinra 100 mg subcutaneously every 6 hours for period of 10 days. For subjects meeting complete response criteria at 5 days, dosing will be decreased to 100 mg twice daily for the remaining 5 days.
  Intervention: Drug: Anakinra
• Placebo Comparator: Control Group
  The control group will receive normal saline placebo subcutaneously every 6 hours for period of 10 days. For subjects meeting complete repsonse criteria at 5 days, dosing wll be decreased to twice daily for the remaining 5 days.
  Intervention: Drug: Normal saline

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Active, not recruiting
• Actual Enrollment (submitted: August 30, 2021): 15
• Original Estimated Enrollment (submitted: April 23, 2020): 20
• Estimated Study Completion Date: April 1, 2023
• Actual Primary Completion Date: December 31, 2021 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

1. 18 years old or older
2. Molecular (pcRNA) diagnosis of SARS-CoV-2 infection
3. Chest imaging studies consistent with Covid-19 pneumonia
4. Hyperferritinemia (>700 ng/ml)
5. History of fever >38 degrees C

6. Any three of the following:

   1. Elevated d-dimer (> 500 ng/ml)
   2. thrombocytopenia (< 130,000/mm3)
   3. leucopenia (WBC <3500/mm3) or lymphopenia (<1000/mm3)
   4. elevated AST or ALT (> 2X ULN)
   5. elevated LDH (> 2X ULN)
   6. CRP > 100 mg/L

Exclusion Criteria:

1. Participation in other investigational treatment protocols for Covid-19 infection
2. Culture confirmed active bacterial infection requiring antibiotic therapy
3. On mechanical ventilation
4. Previous known hypersensitivity reaction to anakinra
5. Previous known hypersensitivity reaction to E Coli derived proteins
6. Pregnant or breast-feeding females

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 80 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT04362111
• Other Study ID Numbers: Chatham-Cytokine Covid-19
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No

IPD Sharing Statement

• Plan to Share IPD: Yes
• Plan Description: Contact PI by e-mail for protocol specifics Submission of results for peer reviewed publication
• Supporting Materials: Study Protocol
• Supporting Materials: Statistical Analysis Plan (SAP)
• Supporting Materials: Clinical Study Report (CSR)
• Time Frame: During study enrollment
• Access Criteria: wchatham@uabmc.edu

• Current Responsible Party: W Winn Chatham, University of Alabama at Birmingham
• Original Responsible Party: Same as current
• Current Study Sponsor: University of Alabama at Birmingham
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Principal Investigator: Walter W Chatham, MD; University of Alabama at Birmingham

• PRS Account: University of Alabama at Birmingham
• Verification Date: January 2023