Early Treatment of Cytokine Storm Syndrome in Covid-19

Phase 3

Completed

• Conditions: Cytokine Storm; COVID-19
• Interventions: Drug: Normal saline; Drug: Anakinra

• Registration Number: NCT04362111
• Lead Sponsor: University of Alabama at Birmingham

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 Timeline

• Study First Submitted: 2020-04-21
• Study First Submitted QC: 2020-04-23
• Study First Posted: 2020-04-24
• Study Start: 2020-08-01
• Primary Completion: 2021-12-31
• Results First Submitted: 2023-05-16
• Study Completion: 2023-06-01
• Status Verified: 2023-08
• Results First Submitted QC: 2023-08-01
• Last Update Submitted: 2023-08-01
• Results First Posted: 2023-08-24
• Last Update Posted: 2023-08-24

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 32

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

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Control Group	Normal saline	The control group will receive normal saline placebo subcutaneously every 6 hours for period of 10 days. For subjects meeting complete response criteria at 5 days, dosing will be decreased to twice daily for the remaining 5 days.
Anakinra Group	Anakinra	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.

Primary Outcome Measures

Name	Time	Method
Subjects Discharged From the Hospital Alive and Without the Need for Mechanical Ventilation.	Variable up to Day 28	Percentage of subjects discharged from hospital alive and who did not require intubation and mechanical ventilation

Secondary Outcome Measures

Name	Time	Method
Percentage of Subjects Without Increase in Oxygen Requirement and no Increase in Oxygen Delivery/Respiratory Support Measures After 48 Hours.	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)
Percentage of Subjects With Resolution of Laboratory Markers of Cytokine Storm Syndrome	Day 10	Normalization or ≥ 75% improvement by Day 10 (120 hours) in each (all) of the following laboratory CSS attributes elevated beyond the normal range at randomization: ferritin, d-dimer, CRP, and LDH.
Percentage of Subjects With 25% Change (Decrease) in Cytokine Storm Markers at 48-72 Hours After Dosing With Study Agent	48 hours after taking initial dose of anakinra/placebo	25% change (decrease) in noted baseline elevations of serum ferritin and CRP measured 48-72 hours after following initial dosing of anakinra/placebo.
Patients Requiring Minimal Oxygen Support at Day 10	0-10 days	Percentage of participants requiring no more than 2 L/min nasal canula oxygen to maintain oxygen saturation \>93% by Day 10
Percentage of Subjects Who Develop Bacterial or Fungal or Non-Covid-19 Viral Infection	Day 0-28	Occurence of new bacterial or fungal or viral infection through the time of hospital discharge or Day 28.
Absence of Supplemental Oxygen Requirement at Day 10	0-10 Days	Percentage of participants able to maintain oxygen saturation \>93% on room air by Day 10

Trial Locations

Locations (1)

University of Alabama at Birmingham; 🇺🇸 Birmingham, Alabama, United States