Early Treatment of Cytokine Storm Syndrome in Covid-19

• ClinicalTrials.gov Identifier: NCT04362111
• Recruitment Status: Recruiting
• First Posted: April 24, 2020
• Last Update Posted: September 11, 2020
• Sponsor: University of Alabama at Birmingham
• Information provided by (Responsible Party): W Winn Chatham, University of Alabama at Birmingham

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Cytokine Storm; COVID-19	Drug: Anakinra; Drug: Normal saline	Phase 3

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 Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 30 participants
• 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
• Official Title: Early Treatment of Cytokine Storm Syndrome in Covid-19
• Actual Study Start Date: July 29, 2020
• Estimated Primary Completion Date: January 2021
• Estimated Study Completion Date: March 2021

Arms and Interventions

Arm	Intervention/treatment
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.	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)
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.	Drug: Normal saline; The control group will receive normal saline placebo subcutaneously every 6-12 hours for period of 10 days; Other Name: NS

Outcome Measures

Primary Outcome Measures :

1. 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

Secondary Outcome Measures :

1. 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.
2. 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)
3. 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
4. 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.
5. 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.
6. Percentage of subjects who develop neutralizing antibody to Covid-19 [ Time Frame: Day 28 ]
   No failure to develop neutralizing antibody to Covid-19 measured at Day 28.

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 80 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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. 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

Contacts and Locations

Contacts

Contact: Walter W Chatham, MD; 800-822-6478; wchatham@uabmc.edu

Contact: Angela Kendrach; 205-996-5602; akendrach@uab.edu

Locations

United States, Alabama

University of Alabama at Birmingham; Recruiting

Birmingham, Alabama, United States, 35294

Contact: Angelia Kendrach akendrach@uabmc.edu

Sponsors and Collaborators

University of Alabama at Birmingham

Investigators

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

More Information

• Responsible Party: W Winn Chatham, Principal Investigator, University of Alabama at Birmingham
• ClinicalTrials.gov Identifier: NCT04362111
• Other Study ID Numbers: Chatham-Cytokine Covid-19
• First Posted: April 24, 2020
• Last Update Posted: September 11, 2020
• Last Verified: September 2020

Individual Participant Data (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; Statistical Analysis Plan (SAP); Clinical Study Report (CSR)
• Time Frame: During study enrollment
• Access Criteria: wchatham@uabmc.edu

• 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

Additional relevant MeSH terms:

Interleukin 1 Receptor Antagonist Protein; Antirheumatic Agents