COVID-19, ARDS
Conditions
Keywords
Corticosteroids, Dexamethasone, COVID-19 Pneumonia, ARDS
Brief summary
This trial will determine the safety and estimate efficacy of targeted corticosteroids in mechanically ventilated patients with the hyper-inflammatory sub phenotype of ARDS due to coronavirus disease 2019 (COVID-19) by implementing a Phase 2A clinical trial.
Detailed description
Acute respiratory distress syndrome (ARDS) is a common, life-threatening pulmonary process which frequently requires mechanical ventilation and has a hospital mortality as high as 40%. No specific pharmacologic therapy has proven efficacy to treat ARDS. Corticosteroids have been investigated as a treatment for ARDS with conflicting results. Two sub phenotypes of ARDS have been described. One is hypo-inflammatory, associated with lower levels of circulating cytokines and therefore greater ventilator free days and a lower mortality. The second sub-phenotype is hyper-inflammatory with elevated cytokine levels, elevated acute phase reactants such as ferritin and c-reactive protein (CRP). Many patients infected with the novel Coronavirus (SARS-CoV-2), the causative agent of CVOID-19, present with an exaggerated inflammatory response which leads to the hyper-inflammatory sub-phenotype of ARDS. These patients may derive great benefit from corticosteroids. Accordingly,this study will determine the safety and estimate efficacy of targeted corticosteroids in mechanically ventilated patients with the hyper-inflammatory sub phenotype of ARDS due to COVID-19 Hypothesis: Early administration of dexamethasone to patients with the hyper-inflammatory sub-phenotype of ARDS due to COVID-19 pneumonia is a safe intervention which increases ventilator free days Approach: This is a single-center, phase 2a, pragmatic, randomized, double-blinded, placebo-controlled study accessing the safety and efficacy of dexamethasone for mechanically ventilated patients with ARDS due to COVID-19 infection. Primary outcome will be ventilator free days at day 28. Understanding the safety and efficacy of corticosteroids in ARDS due to COVID-19 pneumonia could have dramatic implications for critically ill patients. Patients who present with an ARDS sub-type characterized by exaggerated inflammation may particularly benefit from this intervention. Corticosteroids may represent a simple and safe treatment for patients with the most severe form of COVID-19 infection and has the potential to save thousands of lives.
Interventions
Dexamethasone intravenous 20mg daily for 5 days followed by 10mg daily for 5 days
DRUGPlacebos
Placebo delivered intravenously on the same dosing schedule as dexamethasone
Sponsors
University of Colorado, Denver
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Caregiver)
Masking description
Participants confirmed to meet all eligibility criteria who have provided informed consent will be randomized 1:1 to dexamethasone versus placebo. A randomized group assignment will be provided to the investigator or research assistant. Randomization will be performed according to a central randomization scheme and will stratified by site in permuted blocks of varying size.
Intervention model description
Single-center, Phase 2a, pragmatic, randomized, double-blinded, placebo-controlled
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Male or Female Adult ≥ 18 years of age at time of enrollment 2. Laboratory confirmed SARS-CoV-2 infection determined by PCR within 14 days prior to randomization and no alternative explanation for current clinical condition 3. Moderate or Severe ARDS (PaO2:FiO2 ratio ≤ 200mmHg) requiring mechanical ventilation within 7 days prior to randomization 4. Hyper-inflammatory ARDS Sub-Phenotype defined as any one of the following: 1. C-Reactive Protein (CRP) \> 100mg/dL 2. D-Dimer \> 600ng/mL 3. IL-6 \> 10pg/mL 5. Willing and/or able to comply with study-related procedures and assessments 6. Provide informed consent signed by study patient or legally acceptable representative
Exclusion criteria
1. Age \< 18 years 2. In the opinion of the investigator, not expected to survive for more than 48 hours from screening 3. Presence of any of the following abnormal laboratory values at screening 1. Absolute neutrophil count (ANC) \< 2,000mm3 2. Alanine Transferase (ALT) or Aspartate Transferase (AST) \> 5 times upper limit of normal 4. Use of systemic corticosteroid therapy within 7 days of study enrollment 5. Known or suspected active bacterial, fungal or mycobacterial infections including tuberculosis (TB) 6. Participation in a double-blind clinical research study evaluating an investigational product or therapy within 3 months and less than 5 half-lives of investigational product prior to the screening visit. Exception: The use of remdesivir, hydroxychloroquine, or other treatments being used for COVID-19 infection in the context of an open-label study or compassionate use protocol is permitted 7. Any physical examination findings, and/or history of any illness, concomitant medication or recent live vaccines that, in the opinion of the study investigator, might confound the results of the study or pose an additional risk to the patient by their participation in the study 8. Prisoner 9. Pregnancy
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Ventilator Free Days (VFD) at Day 28 | 28 Days | Total number of ventilator free days to day 28 of hospitalization. If a patient dies prior to day 28, they will be counted as zero ventilator free days. Follow up will be performed via phone or electronically to determine ventilator free status of those patients discharged prior to day 28. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Clinical Status at day 28 as measured by WHO 7-point ordinal scale | 28 Days | — |
| In-Hospital Mortality at day 28 | 28 Days | — |
| In-Hospital Mortality at day 90 | 90 Days | — |
| Time to Mortality to day 28 | 28 Days | — |
| ICU-free days to day 28 | 28 Days | — |
| Hospital Length of Stay among survivors to day 90 | 90 Days | — |
| Severity of ARDS to day 10 | 10 Days | — |
| Days to resolution of fever | 28 Days | — |
| Clinical Status at day 14 as measured by World Health Organization (WHO) 7-point ordinal scale. | 14 Days | 1\. Not hospitalized, no limitations on activities; 2. Not hospitalized, limitation on activities; 3. Hospitalized, not requiring supplemental oxygen; 4. Hospitalized, requiring supplemental oxygen; 5. Hospitalized, on non-invasive ventilation or high flow oxygen devices; 6. Hospitalized, on invasive mechanical ventilation or ECMO; 7. Death. |
| Vasopressor-free days to day 28 | 28 Days | — |
| Renal replacement-free days to day 28 | 28 Days | — |
| Duration of mechanical ventilation to day 28 | 28 Days | — |
| Oxygenation-free days to day 28 | 28 Days | — |
| Incidence of New Mechanical Ventilation to day 28 | 28 Days | — |
| Change in sequential organ failure assessment (SOFA) score from baseline to day 10 | 10 Days | — |
| In-hospital adverse events to day 28 | 28 Days | — |
| Discontinuation of study drug infusion | 10 Days | — |
| Change in C-Reactive Protein (CRP) level from baseline to day 10 | 10 Days | — |
Outcome results
None listed