COVID-19, Cytokine Storm
Conditions
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.
Interventions
DRUGAnakinra
The active treatment group will receive anakinra 100 mg subcutaneously every 6-12 hours for a period of 10 days
DRUGNormal saline
The control group will receive normal saline placebo subcutaneously every 6-12 hours for period of 10 days
Sponsors
University of Alabama at Birmingham
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Masking description
Investigator, care provider, and participant blinded
Intervention model description
Two parallel treatment arms
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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) |
| 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 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. |
| 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 |
| 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. |
Countries
United States
Participant flow
Recruitment details
Subjects for enrollment were identified by pre-screening all patients admitted to the University of Alabama Hospital for treatment of Covid-19 pneumonia from August 1, 2020-January 15, 2021. Patients who were admitted with a new requirement for supplemental oxygen to maintain arterial oxygen saturation \>93% but not yet requiring mechanical ventilation and who had admission laboratory studies meeting study inclusion criteria for evidence of inflammation were approached for enrollment.
Pre-assignment details
Patients who met inclusion/exclusion criteria and who had ongoing or increasing oxygen requirement were consented and enrolled. Once consented and enrolled, all subjects were randomly assigned to the two treatment groups. No participants were excluded after enrollment and randomization. Two subjects withdrew consent within 48 hours of enrollment.
Participants by arm
| Arm | Count |
|---|---|
| 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.
Anakinra: The active treatment group will receive anakinra 100 mg subcutaneously every 6-12 hours for a period of 10 days | 15 |
| 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.
Normal saline: The control group will receive normal saline placebo subcutaneously every 6-12 hours for period of 10 days | 15 |
| Total | 30 |
Baseline characteristics
| Characteristic | Control Group | Total | Anakinra Group |
|---|---|---|---|
| Age, Continuous | 61.8 years STANDARD_DEVIATION 12.2 | 63.0 years STANDARD_DEVIATION 10.2 | 64.2 years STANDARD_DEVIATION 8.2 |
| Co-morbidities Cardiovascular Disease | 3 Participants | 7 Participants | 4 Participants |
| Co-morbidities Diabetes | 3 Participants | 8 Participants | 5 Participants |
| Co-morbidities Hypertension | 10 Participants | 21 Participants | 11 Participants |
| Number of Participants that Smoke | 5 Participants | 11 Participants | 6 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 5 Participants | 9 Participants | 4 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) White | 9 Participants | 20 Participants | 11 Participants |
| Sex: Female, Male Female | 5 Participants | 10 Participants | 5 Participants |
| Sex: Female, Male Male | 10 Participants | 20 Participants | 10 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 4 / 15 | 4 / 15 |
| other Total, other adverse events | 14 / 15 | 13 / 15 |
| serious Total, serious adverse events | 9 / 15 | 7 / 15 |
Outcome results
Primary
Subjects Discharged From the Hospital Alive and Without the Need for Mechanical Ventilation.
Percentage of subjects discharged from hospital alive and who did not require intubation and mechanical ventilation
Time frame: Variable up to Day 28
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Anakinra Group | Subjects Discharged From the Hospital Alive and Without the Need for Mechanical Ventilation. | 10 Participants |
| Control Group | Subjects Discharged From the Hospital Alive and Without the Need for Mechanical Ventilation. | 10 Participants |
Secondary
Absence of Supplemental Oxygen Requirement at Day 10
Percentage of participants able to maintain oxygen saturation \>93% on room air by Day 10
Time frame: 0-10 Days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Anakinra Group | Absence of Supplemental Oxygen Requirement at Day 10 | 4 Participants |
| Control Group | Absence of Supplemental Oxygen Requirement at Day 10 | 9 Participants |
Secondary
Patients Requiring Minimal Oxygen Support at Day 10
Percentage of participants requiring no more than 2 L/min nasal canula oxygen to maintain oxygen saturation \>93% by Day 10
Time frame: 0-10 days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Anakinra Group | Patients Requiring Minimal Oxygen Support at Day 10 | 8 Participants |
| Control Group | Patients Requiring Minimal Oxygen Support at Day 10 | 9 Participants |
Secondary
Percentage of Subjects Who Develop Bacterial or Fungal or Non-Covid-19 Viral Infection
Occurence of new bacterial or fungal or viral infection through the time of hospital discharge or Day 28.
Time frame: Day 0-28
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Anakinra Group | Percentage of Subjects Who Develop Bacterial or Fungal or Non-Covid-19 Viral Infection | 1 Participants |
| Control Group | Percentage of Subjects Who Develop Bacterial or Fungal or Non-Covid-19 Viral Infection | 0 Participants |
Secondary
Percentage of Subjects With 25% Change (Decrease) in Cytokine Storm Markers at 48-72 Hours After Dosing With Study Agent
25% change (decrease) in noted baseline elevations of serum ferritin and CRP measured 48-72 hours after following initial dosing of anakinra/placebo.
Time frame: 48 hours after taking initial dose of anakinra/placebo
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Anakinra Group | Percentage of Subjects With 25% Change (Decrease) in Cytokine Storm Markers at 48-72 Hours After Dosing With Study Agent | 6 Participants |
| Control Group | Percentage of Subjects With 25% Change (Decrease) in Cytokine Storm Markers at 48-72 Hours After Dosing With Study Agent | 8 Participants |
Secondary
Percentage of Subjects Without Increase in Oxygen Requirement and no Increase in Oxygen Delivery/Respiratory Support Measures After 48 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)
Time frame: Day 2 (48 hours)-Day 10 (240 hours)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Anakinra Group | Percentage of Subjects Without Increase in Oxygen Requirement and no Increase in Oxygen Delivery/Respiratory Support Measures After 48 Hours. | 8 Participants |
| Control Group | Percentage of Subjects Without Increase in Oxygen Requirement and no Increase in Oxygen Delivery/Respiratory Support Measures After 48 Hours. | 9 Participants |
Secondary
Percentage of Subjects With Resolution of Laboratory Markers of Cytokine Storm Syndrome
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.
Time frame: Day 10
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Anakinra Group | Percentage of Subjects With Resolution of Laboratory Markers of Cytokine Storm Syndrome | 0 Participants |
| Control Group | Percentage of Subjects With Resolution of Laboratory Markers of Cytokine Storm Syndrome | 7 Participants |