Acute Respiratory Distress Syndrome, Coronavirus Infection
Conditions
Keywords
COVID-19, ARDS
Brief summary
The purpose of this study is to evaluate the efficacy of vadadustat for the prevention and treatment of acute respiratory distress syndrome (ARDS) in hospitalized patients with Coronavirus Disease 2019 (COVID-19).
Interventions
DRUGvadadustat
Participants will receive vadadustat once daily for 14 days.
DRUGplacebo
Participants will receive matching placebo once daily for 14 days.
Sponsors
Akebia Therapeutics Inc.
United States Department of Defense
The University of Texas Health Science Center, Houston
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Laboratory-confirmed diagnosis of COVID-19 by detection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA by Reverse transcription polymerase chain reaction (RT-PCR) from any specimen respiratory * Admitted to the hospital within 36 hours * Oxygen saturation of hemoglobin by pulse oximetry at room air ≤94% * For patients admitted WITH respiratory symptoms, enrollment must occur within 36 hours of hospital admission. If the patient is admitted to the hospital with normal saturations, but develops respiratory symptoms DURING their hospital stay, enrollment may occur within 24 hours of desaturation to 94% or less on room air * Understands the procedures and requirements of the study and provides written informed consent and authorization for protected health information disclosure
Exclusion criteria
* Hypersensitivity to vadadustat or any of its excipients * Placed on mechanical ventilation before randomization * Hemoglobin above the gender-specific upper limit of normal (ULN) at randomization: 16 g/dL for females and 18 g/dL for males * Patients who have erythrocytosis or polycythemia vera * Patient taking Probenecid, lopinavir or ritonavir * Women who are pregnant or breastfeeding, or positive pregnancy test before randomization * Patients not on maintenance dialysis with eGFC \< 31 ml/min * Patients who have received a solid organ transplant, heart, kidney, liver or lung * Patients who are prisoners * Patients who are currently Do Not Resuscitate (DNR) or Do Not Intubate (DNI) * Patients with modified Rankin scale of 3 or greater * Patient who are currently enrolled in any other interventional clinical trial
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Who Are Classified 8 (Dead), 7 (Hospitalized, on Invasive Mechanical Ventilation or ECMO), or 6 (Hospitalized, on Non-invasive Ventilation or High Flow Oxygen Devices) on the NIAID Ordinal Scale | day 14 | National Institute of Allergy and Infectious Disease Ordinal Scale (NIAID-OS): 8 - Death 7 - Hospitalized, on invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO) 6 - Hospitalized, on non-invasive ventilation or high flow oxygen devices 5 - Hospitalized, requiring supplemental oxygen 4 - Hospitalized, not requiring supplemental oxygen - requiring ongoing care (COVID-19 related or otherwise) 3 - Hospitalized, not requiring supplemental oxygen - no longer requires ongoing medical care 2 - Not hospitalized, limitation on activities and/or requiring home oxygen 1 - Not hospitalized, no limitations on activities |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With a Total Score of 0 on the Modified Sequential Organ Failure Assessment (MSOFA) Scale | day 14 | Modified Sequential Organ Failure Assessment (MSOFA) scale: Each of 5 organ systems is given a score of 0 to 4.The MSOFA scale total score is the sum of the score for the 5 organ systems. Total score ranges from 0 to 20, a higher score indicates a worse outcome. Discharged patients will be assigned a score of 0 and dead patients a score of 20. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Score on the Modified Sequential Organ Failure Assessment (MSOFA) Scale | day 7 | Modified Sequential Organ Failure Assessment (MSOFA) scale: Each of 5 organ systems is given a score of 0 to 4, as detailed below. The MSOFA scale total score is the sum of the score for the 5 organ systems. Discharged patients will be assigned a score of 0 and dead patients a score of 20. * Respiratory oxygen saturation(SpO2)/concentration of oxygen that a person inhales(FiO2): 0 (\> 400); 1 (≤ 400); 2 (≤ 315); 3 (≤ 235); 4 (≤ 150) * Liver: 0 (No scleral icterus or jaundice); 3 (Scleral icterus or jaundice) * Cardiovascular, hypotension: 0 (No hypotension); 1 (MAP \< 70 mm Hg); 2 (Dopamine ≤ 5 or dobutamine any dose); 3 (Dopamine \> 5, Epinephrine ≤ 0.1, Norepinephrine ≤ 0.1); 4 (Dopamine \> 15, Epinephrine \> 0.1, Norepinephrine \> 0.1) * Central Nervous System (CNS), Glasgow Coma Score: 0 (15), 1 (13 - 14); 2 (10 - 12); 3 (6 - 9); 4 (\< 6) * Renal, Creatinine mg/dL: 0 (\< 1.2); 1 (1.2 - 1.9); 2 (2.0 - 3.4); 3 (3.5 - 4.9); 4 (\> 5.0) |
| Ventilator-free Survival | day 7 | — |
| Time to Hospital Discharge | From the time of hospital admission to hospital discharge (about 7 days) | — |
| Number of Participants With Acute Kidney Injury | day 7 | — |
| Overall Survival | day 7 | — |
| Number of Participants With Hypotension | day 7 | Hypotension is defined as Mean Arterial Pressure (MAP) \<70 mm Hg or requirement for inotropes or vasopressors to maintain blood pressure. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Vadadustat vadadustat: Participants will receive vadadustat once daily for 14 days. | 221 |
| Placebo placebo: Participants will receive matching placebo once daily for 14 days. | 227 |
| Total | 448 |
Baseline characteristics
| Characteristic | Total | Vadadustat | Placebo |
|---|---|---|---|
| Age, Continuous | 50.9 years STANDARD_DEVIATION 14.7 | 51.1 years STANDARD_DEVIATION 14.8 | 50.7 years STANDARD_DEVIATION 14.7 |
| Body Mass Index | 32.2 kilograms per meter squared | 31.6 kilograms per meter squared | 32.8 kilograms per meter squared |
| Days since onset of COVID symptoms | 7 days | 7 days | 7 days |
| Ethnicity (NIH/OMB) Hispanic or Latino | 309 Participants | 158 Participants | 151 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 139 Participants | 63 Participants | 76 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Number of Participants with a history of hypertension | 165 Participants | 74 Participants | 91 Participants |
| Number of Participants with history of type 2 diabetes | 135 Participants | 62 Participants | 73 Participants |
| Oxygen Saturation to Fraction of Inspired Oxygen (SpO2/FiO2) Ratio | 220.8 SpO2/FiO2 Ratio STANDARD_DEVIATION 93 | 217.4 SpO2/FiO2 Ratio STANDARD_DEVIATION 91.8 | 224.1 SpO2/FiO2 Ratio STANDARD_DEVIATION 94.2 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 25 Participants | 13 Participants | 12 Participants |
| Race (NIH/OMB) Black or African American | 47 Participants | 21 Participants | 26 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 | 38 Participants | 19 Participants | 19 Participants |
| Race (NIH/OMB) White | 338 Participants | 168 Participants | 170 Participants |
| Region of Enrollment United States | 448 participants | 221 participants | 227 participants |
| Score ≥ 4 on the Modified Sequential Organ Failure Assessment (MSOFA) Scale [1] | 142 Participants | 69 Participants | 73 Participants |
| Score on the Modified Sequential Organ Failure Assessment (MSOFA) Scale | 2.73 score on a scale STANDARD_DEVIATION 1.18 | 2.73 score on a scale STANDARD_DEVIATION 1.17 | 2.74 score on a scale STANDARD_DEVIATION 1.19 |
| Score on the National Institute of Allergy and Infectious Disease Ordinal Scale (NIAID-OS) | 5.3 score on a scale STANDARD_DEVIATION 0.5 | 5.3 score on a scale STANDARD_DEVIATION 0.5 | 5.3 score on a scale STANDARD_DEVIATION 0.5 |
| Sex: Female, Male Female | 162 Participants | 79 Participants | 83 Participants |
| Sex: Female, Male Male | 286 Participants | 142 Participants | 144 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 19 / 221 | 19 / 227 |
| other Total, other adverse events | 109 / 221 | 116 / 227 |
| serious Total, serious adverse events | 61 / 221 | 73 / 227 |
Outcome results
Primary
Number of Participants Who Are Classified 8 (Dead), 7 (Hospitalized, on Invasive Mechanical Ventilation or ECMO), or 6 (Hospitalized, on Non-invasive Ventilation or High Flow Oxygen Devices) on the NIAID Ordinal Scale
National Institute of Allergy and Infectious Disease Ordinal Scale (NIAID-OS): 8 - Death 7 - Hospitalized, on invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO) 6 - Hospitalized, on non-invasive ventilation or high flow oxygen devices 5 - Hospitalized, requiring supplemental oxygen 4 - Hospitalized, not requiring supplemental oxygen - requiring ongoing care (COVID-19 related or otherwise) 3 - Hospitalized, not requiring supplemental oxygen - no longer requires ongoing medical care 2 - Not hospitalized, limitation on activities and/or requiring home oxygen 1 - Not hospitalized, no limitations on activities
Time frame: day 14
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Vadadustat | Number of Participants Who Are Classified 8 (Dead), 7 (Hospitalized, on Invasive Mechanical Ventilation or ECMO), or 6 (Hospitalized, on Non-invasive Ventilation or High Flow Oxygen Devices) on the NIAID Ordinal Scale | 43 Participants |
| Placebo | Number of Participants Who Are Classified 8 (Dead), 7 (Hospitalized, on Invasive Mechanical Ventilation or ECMO), or 6 (Hospitalized, on Non-invasive Ventilation or High Flow Oxygen Devices) on the NIAID Ordinal Scale | 53 Participants |
Comparison: Trial used Bayesian analysis for superiority. Hypothesis Testing for Primary Outcome: Among adult hospital admissions with lab-confirmed diagnosis of COVID-19, vadadustat 900 mg will demonstrate superiority to placebo as defined by a lower probability, at treatment day 14, of death (8) or hospitalization, on invasive mechanical ventilation or ECMO (7) or hospitalization, on non-invasive ventilation or high flow oxygen devices (6) on the NIAID-OS. See Statistical Analysis Plan for more details.95% CI: [-0.084, 0.009]
Secondary
Number of Participants With a Total Score of 0 on the Modified Sequential Organ Failure Assessment (MSOFA) Scale
Modified Sequential Organ Failure Assessment (MSOFA) scale: Each of 5 organ systems is given a score of 0 to 4.The MSOFA scale total score is the sum of the score for the 5 organ systems. Total score ranges from 0 to 20, a higher score indicates a worse outcome. Discharged patients will be assigned a score of 0 and dead patients a score of 20.
Time frame: day 14
Population: Data were not collected for 2 participants in the vadadustat arm.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Vadadustat | Number of Participants With a Total Score of 0 on the Modified Sequential Organ Failure Assessment (MSOFA) Scale | 156 Participants |
| Placebo | Number of Participants With a Total Score of 0 on the Modified Sequential Organ Failure Assessment (MSOFA) Scale | 157 Participants |
Comparison: Trial used Bayesian analysis for superiority. Hypothesis Testing for Secondary Outcome: Among adult hospital admissions with lab-confirmed diagnosis of COVID-19, vadadustat 900 mg will demonstrate superiority to placebo as defined by a higher probability, at treatment day 14, of recovery on the MSOFA scale (MSOFA = 0).95% CI: [0.92, 1.1]
Other Pre-specified
Number of Participants With Acute Kidney Injury
Time frame: day 14
Other Pre-specified
Number of Participants With Acute Kidney Injury
Time frame: day 7
Other Pre-specified
Number of Participants With Hypotension
Hypotension is defined as Mean Arterial Pressure (MAP) \<70 mm Hg or requirement for inotropes or vasopressors to maintain blood pressure.
Time frame: day 7
Other Pre-specified
Number of Participants With Hypotension
Hypotension is defined as Mean Arterial Pressure (MAP) \<70 mm Hg or requirement for inotropes or vasopressors to maintain blood pressure.
Time frame: day 14
Other Pre-specified
Overall Survival
Time frame: day 14
Other Pre-specified
Overall Survival
Time frame: day 7
Other Pre-specified
Score on the Modified Sequential Organ Failure Assessment (MSOFA) Scale
Modified Sequential Organ Failure Assessment (MSOFA) scale: Each of 5 organ systems is given a score of 0 to 4, as detailed below. The MSOFA scale total score is the sum of the score for the 5 organ systems. Discharged patients will be assigned a score of 0 and dead patients a score of 20. * Respiratory oxygen saturation(SpO2)/concentration of oxygen that a person inhales(FiO2): 0 (\> 400); 1 (≤ 400); 2 (≤ 315); 3 (≤ 235); 4 (≤ 150) * Liver: 0 (No scleral icterus or jaundice); 3 (Scleral icterus or jaundice) * Cardiovascular, hypotension: 0 (No hypotension); 1 (MAP \< 70 mm Hg); 2 (Dopamine ≤ 5 or dobutamine any dose); 3 (Dopamine \> 5, Epinephrine ≤ 0.1, Norepinephrine ≤ 0.1); 4 (Dopamine \> 15, Epinephrine \> 0.1, Norepinephrine \> 0.1) * Central Nervous System (CNS), Glasgow Coma Score: 0 (15), 1 (13 - 14); 2 (10 - 12); 3 (6 - 9); 4 (\< 6) * Renal, Creatinine mg/dL: 0 (\< 1.2); 1 (1.2 - 1.9); 2 (2.0 - 3.4); 3 (3.5 - 4.9); 4 (\> 5.0)
Time frame: day 7
Other Pre-specified
Score on the Modified Sequential Organ Failure Assessment (MSOFA) Scale
Modified Sequential Organ Failure Assessment (MSOFA) scale: Each of 5 organ systems is given a score of 0 to 4, as detailed below. The MSOFA scale total score is the sum of the score for the 5 organ systems. Discharged patients will be assigned a score of 0 and dead patients a score of 20. * Respiratory oxygen saturation(SpO2)/concentration of oxygen that a person inhales(FiO2): 0 (\> 400); 1 (≤ 400); 2 (≤ 315); 3 (≤ 235); 4 (≤ 150) * Liver: 0 (No scleral icterus or jaundice); 3 (Scleral icterus or jaundice) * Cardiovascular, hypotension: 0 (No hypotension); 1 (MAP \< 70 mm Hg); 2 (Dopamine ≤ 5 or dobutamine any dose); 3 (Dopamine \> 5, Epinephrine ≤ 0.1, Norepinephrine ≤ 0.1); 4 (Dopamine \> 15, Epinephrine \> 0.1, Norepinephrine \> 0.1) * Central Nervous System (CNS), Glasgow Coma Score: 0 (15), 1 (13 - 14); 2 (10 - 12); 3 (6 - 9); 4 (\< 6) * Renal, Creatinine mg/dL: 0 (\< 1.2); 1 (1.2 - 1.9); 2 (2.0 - 3.4); 3 (3.5 - 4.9); 4 (\> 5.0)
Time frame: day 14
Other Pre-specified
Time to Hospital Discharge
Time frame: From the time of hospital admission to hospital discharge (about 7 days)
Other Pre-specified
Ventilator-free Survival
Time frame: day 14
Other Pre-specified
Ventilator-free Survival
Time frame: day 7