Targeted Steroids for ARDS Due to COVID-19 Pneumonia: A Pilot Randomized Clinical Trial

• ClinicalTrials.gov Identifier: NCT04360876
• Recruitment Status: Withdrawn
• First Posted: April 24, 2020
• Last Update Posted: October 28, 2020
• Sponsor: University of Colorado, Denver
• Information provided by (Responsible Party): University of Colorado, Denver

Tracking Information

• First Submitted Date: April 22, 2020
• First Posted Date: April 24, 2020
• Last Update Posted Date: October 28, 2020
• Estimated Study Start Date: September 1, 2020
• Estimated Primary Completion Date: December 31, 2020 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: April 22, 2020)

Ventilator Free Days (VFD) at Day 28 [ Time Frame: 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.

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: April 22, 2020)

• Clinical Status at day 14 as measured by World Health Organization (WHO) 7-point ordinal scale. [ Time Frame: 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.
• Clinical Status at day 28 as measured by WHO 7-point ordinal scale [ Time Frame: 28 Days ]
• In-Hospital Mortality at day 28 [ Time Frame: 28 Days ]
• In-Hospital Mortality at day 90 [ Time Frame: 90 Days ]
• Time to Mortality to day 28 [ Time Frame: 28 Days ]
• ICU-free days to day 28 [ Time Frame: 28 Days ]
• Hospital Length of Stay among survivors to day 90 [ Time Frame: 90 Days ]
• Severity of ARDS to day 10 [ Time Frame: 10 Days ]
• Days to resolution of fever [ Time Frame: 28 Days ]
• Change in C-Reactive Protein (CRP) level from baseline to day 10 [ Time Frame: 10 Days ]
• Vasopressor-free days to day 28 [ Time Frame: 28 Days ]
• Renal replacement-free days to day 28 [ Time Frame: 28 Days ]
• Duration of mechanical ventilation to day 28 [ Time Frame: 28 Days ]
• Oxygenation-free days to day 28 [ Time Frame: 28 Days ]
• Incidence of New Mechanical Ventilation to day 28 [ Time Frame: 28 Days ]
• Change in sequential organ failure assessment (SOFA) score from baseline to day 10 [ Time Frame: 10 Days ]
• In-hospital adverse events to day 28 [ Time Frame: 28 Days ]
• Discontinuation of study drug infusion [ Time Frame: 10 Days ]

• Original Secondary Outcome Measures: Same as current
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Targeted Steroids for ARDS Due to COVID-19 Pneumonia: A Pilot Randomized Clinical Trial
• Official Title: Targeted Steroids for ARDS Due to COVID-19 Pneumonia: A Pilot Randomized Clinical Trial
• 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.

• Study Type: Interventional
• Study Phase: Phase 2

Study Design

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

Single-center, Phase 2a, pragmatic, randomized, double-blinded, placebo-controlled

Masking: Double (Participant, Care Provider)
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.

Primary Purpose: Treatment

Condition

• COVID-19
• ARDS

Intervention

• Drug: Dexamethasone injection
  Dexamethasone intravenous 20mg daily for 5 days followed by 10mg daily for 5 days
• Drug: Placebos
  Placebo delivered intravenously on the same dosing schedule as dexamethasone

Study Arms

• Experimental: Dexamethasone
  Patients assigned to the dexamethasone arm will receive an intravenous dose of 20 mg once daily from day 1 to day 5 which will be reduced to 10mg once daily from day 6 to day 10. Intravenous infusion bags divided into 10 doses will be provided at randomization by the investigational pharmacy. The time from randomization to time for first medication administration will be 4 hours or less. All infusions - dexamethasone and placebo - will be manufactured by the investigational pharmacy at the University of Colorado.
  Intervention: Drug: Dexamethasone injection
• Placebo Comparator: Placebo
  Participants randomized to the control group will received placebo intravenously for 10 days, one dose per day. Intravenous infusion bags divided into 10 doses will be provided at randomization by the investigational pharmacy. The placebo infusion bags will be as similar as possible to the dexamethasone infusion bags to ensure blinding.
  Intervention: Drug: Placebos

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Withdrawn
• Actual Enrollment (submitted: October 26, 2020): 0
• Original Estimated Enrollment (submitted: April 22, 2020): 90
• Estimated Study Completion Date: January 30, 2021
• Estimated Primary Completion Date: December 31, 2020 (Final data collection date for primary outcome measure)

Eligibility Criteria

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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Not Provided

Administrative Information

• NCT Number: NCT04360876
• Other Study ID Numbers: 20-0811
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: No
• 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: No
• Plan Description: No Plan

• Current Responsible Party: University of Colorado, Denver
• Original Responsible Party: Same as current
• Current Study Sponsor: University of Colorado, Denver
• Original Study Sponsor: Same as current
• Collaborators: Not Provided
• Investigators: Not Provided
• PRS Account: University of Colorado, Denver
• Verification Date: October 2020