COVID-19
Conditions
Keywords
COVID-19, multi-organ failure, acute kidney injury
Brief summary
The purpose of this study is to determine if administration of angiotensin-(1-7) (TXA127) prevents acute kidney injury and deterioration into multi-organ failure in patients with severe COVID-19. Participants will undergo a 10-day treatment with either placebo or study drug. The drug will be administered intravenously for 3 hours once each day for 10 days consecutively.
Detailed description
Corona virus disease 2019 (COVID-19) has been associated with severe respiratory and multiorgan failure. Research shows that COVID-19 reduces levels of angiotensin-converting enzyme-2 (ACE-2), an enzyme that converts angiotensin II to angiotensin 1-7 (known as TXA127). COVID-19 reduces levels of ACE-2 and therefore angiotensin 1-7 and as a result, angiotensin II levels are going to be increased. Many clinical observations in COVID-19 have shown the high incidence of acute kidney injury that may be due to excessive levels of angiotensin II. The investigators hypothesize that administration of angiotensin (1-7) replaces levels of ACE-2 in COVID-19 and thereby ameliorates deterioration of multi-organ failure and specifically acute kidney injury.
Interventions
DRUGTXA127
0.5 mg/kg per day
DRUGPlacebo
0.5 mg/kg per day
Sponsors
Constant Therapeutics LLC
Columbia University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Intervention model description
Double-blinded, placebo-control, randomized clinical trial
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Severe COVID-19: Adult patients admitted to the hospital through the Emergency Department (ED) requiring oxygen therapy (any level) to maintain oxygen saturation (SaO2) \> 90% * COVID positive by polymerase chain reaction (PCR) on hospital admission * Hospitalized patients aged 18 years or greater
Exclusion criteria
* Pre-existing chronic kidney disease * New use of or change in dose of ACE-inhibitors or angiotensin receptor blocker (ARB) within the last 6 months * Acute kidney injury at the time of enrollment defined as either increase pf serum creatinine by more than 50% or 0.3 mg/dL above baseline or estimated creatinine clearance (by MDRD) of less than 60 ml/min (if no baseline serum creatinine available) * Pregnant and breastfeeding women * Contraindicated medications: new use or change of medications from start of trial (start of an ACE inhibitor or ARB within 6 months of trial).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change of Serum Creatinine | Day 1 and Day 10 | Calculated from baseline (at enrollment) to end of study |
| Number of Participants Requiring Intubation | From Day 1 to Day 10 | — |
Secondary
| Measure | Time frame |
|---|---|
| Number of Participants Requiring a Vasopressors | Up to Day 10 |
| Percent Change in Supplemental Oxygen Requirements | Day 1 and Day 10 |
| Mortality | Day 1 to Day 10 |
| Cytokine Levels on the Day of Drug/TXA Administration | Day 1 |
| Cytokine Levels on the Day 5 of Drug/TXA Administration | Day 5 |
| Days of Hospital Stay and Drug Administration | Day 1 to Day 10 |
| Number of Participants Requiring Dialysis | Up to Day 10 |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| TXA127 Participants will receive one 3-hour dosage (0.5 mg/kg per day), intravenously, for 10 days consecutively (or until discharge if less than 10 days).
TXA127: 0.5 mg/kg per day | 11 |
| Placebo Participants will receive one 3-hour dosage (0.5 mg/kg per day), intravenously, for 10 days consecutively (or until discharge if less than 10 days).
Placebo: 0.5 mg/kg per day | 9 |
| Total | 20 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Physician Decision | 2 | 1 |
| Overall Study | Withdrawal by Subject | 3 | 1 |
Baseline characteristics
| Characteristic | TXA127 | Placebo | Total |
|---|---|---|---|
| Age, Continuous | 55 years | 55 years | 55 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 8 Participants | 7 Participants | 15 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 3 Participants | 1 Participants | 4 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 1 Participants | 1 Participants |
| Oxygen at randomization High flow nasal cannula | 3 Participants | 1 Participants | 4 Participants |
| Oxygen at randomization Nasal cannula | 7 Participants | 8 Participants | 15 Participants |
| Oxygen at randomization Non-invasive ventilation/BiPAP | 1 Participants | 0 Participants | 1 Participants |
| Oxygen at randomization Room air | 0 Participants | 0 Participants | 0 Participants |
| Region of Enrollment United States | 11 Participants | 9 Participants | 20 Participants |
| Sex: Female, Male Female | 2 Participants | 5 Participants | 7 Participants |
| Sex: Female, Male Male | 9 Participants | 4 Participants | 13 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 2 / 11 | 1 / 9 |
| other Total, other adverse events | 7 / 11 | 5 / 9 |
| serious Total, serious adverse events | 3 / 11 | 2 / 9 |
Outcome results
Primary
Change of Serum Creatinine
Calculated from baseline (at enrollment) to end of study
Time frame: Day 1 and Day 10
Population: Only subjects who received at least 1 complete dose of drug/placebo were included in the data analysis - which is not the same as those who completed the study as seen under Participant Flow. This included 11 out of 11 in the TXA127 group and 9 out of 11 in the Placebo group.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| TXA127 | Change of Serum Creatinine | 0.92 mg/dL |
| Placebo | Change of Serum Creatinine | 0.70 mg/dL |
Primary
Number of Participants Requiring Intubation
Time frame: From Day 1 to Day 10
Population: Only subjects who received at least 1 complete dose of drug/placebo were included in the data analysis. This included 11 out of 11 in the TXA127 group and 9 out of 11 in the Placebo group.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| TXA127 | Number of Participants Requiring Intubation | 3 Participants |
| Placebo | Number of Participants Requiring Intubation | 2 Participants |
Secondary
Cytokine Levels on the Day 5 of Drug/TXA Administration
Time frame: Day 5
Population: Only subjects who received at least 1 complete dose of drug/placebo were included in the data analysis. This included 11 out of 11 in the TXA127 group and 9 out of 11 in the Placebo group.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| TXA127 | Cytokine Levels on the Day 5 of Drug/TXA Administration | Interferon-γ | 0.88 pg/ml |
| TXA127 | Cytokine Levels on the Day 5 of Drug/TXA Administration | IL-1β | 14.4 pg/ml |
| TXA127 | Cytokine Levels on the Day 5 of Drug/TXA Administration | IL-1Ra | 17.77 pg/ml |
| TXA127 | Cytokine Levels on the Day 5 of Drug/TXA Administration | IL-2 | 0.20 pg/ml |
| TXA127 | Cytokine Levels on the Day 5 of Drug/TXA Administration | IL-4 | 0.09 pg/ml |
| TXA127 | Cytokine Levels on the Day 5 of Drug/TXA Administration | IL-5 | 3.36 pg/ml |
| TXA127 | Cytokine Levels on the Day 5 of Drug/TXA Administration | IL-6 | 12.88 pg/ml |
| TXA127 | Cytokine Levels on the Day 5 of Drug/TXA Administration | IL-8 | 24.5 pg/ml |
| TXA127 | Cytokine Levels on the Day 5 of Drug/TXA Administration | TNF-α | 31.1 pg/ml |
| TXA127 | Cytokine Levels on the Day 5 of Drug/TXA Administration | IL-10 | 2.46 pg/ml |
| TXA127 | Cytokine Levels on the Day 5 of Drug/TXA Administration | IL-12p40 | 45.40 pg/ml |
| TXA127 | Cytokine Levels on the Day 5 of Drug/TXA Administration | IL-12p70 | 1.28 pg/ml |
| TXA127 | Cytokine Levels on the Day 5 of Drug/TXA Administration | IL-13 | 10.71 pg/ml |
| TXA127 | Cytokine Levels on the Day 5 of Drug/TXA Administration | MCP-1 | 218 pg/ml |
| Placebo | Cytokine Levels on the Day 5 of Drug/TXA Administration | IL-6 | 1.34 pg/ml |
| Placebo | Cytokine Levels on the Day 5 of Drug/TXA Administration | MCP-1 | 237 pg/ml |
| Placebo | Cytokine Levels on the Day 5 of Drug/TXA Administration | Interferon-γ | 0.78 pg/ml |
| Placebo | Cytokine Levels on the Day 5 of Drug/TXA Administration | IL-12p70 | 1.21 pg/ml |
| Placebo | Cytokine Levels on the Day 5 of Drug/TXA Administration | IL-1β | 50.6 pg/ml |
| Placebo | Cytokine Levels on the Day 5 of Drug/TXA Administration | IL-8 | 14.3 pg/ml |
| Placebo | Cytokine Levels on the Day 5 of Drug/TXA Administration | IL-1Ra | 7.38 pg/ml |
| Placebo | Cytokine Levels on the Day 5 of Drug/TXA Administration | IL-12p40 | 29.8 pg/ml |
| Placebo | Cytokine Levels on the Day 5 of Drug/TXA Administration | IL-2 | 0.91 pg/ml |
| Placebo | Cytokine Levels on the Day 5 of Drug/TXA Administration | TNF-α | 42.1 pg/ml |
| Placebo | Cytokine Levels on the Day 5 of Drug/TXA Administration | IL-4 | 0.74 pg/ml |
| Placebo | Cytokine Levels on the Day 5 of Drug/TXA Administration | IL-13 | 11.4 pg/ml |
| Placebo | Cytokine Levels on the Day 5 of Drug/TXA Administration | IL-5 | 0.99 pg/ml |
| Placebo | Cytokine Levels on the Day 5 of Drug/TXA Administration | IL-10 | 4.19 pg/ml |
Secondary
Cytokine Levels on the Day of Drug/TXA Administration
Time frame: Day 1
Population: Only subjects who received at least 1 complete dose of drug/placebo were included in the data analysis. This included 11 out of 11 in the TXA127 group and 9 out of 11 in the Placebo group.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| TXA127 | Cytokine Levels on the Day of Drug/TXA Administration | MCP-1 | 345 pg/ml |
| TXA127 | Cytokine Levels on the Day of Drug/TXA Administration | Interferon-γ | 1.44 pg/ml |
| TXA127 | Cytokine Levels on the Day of Drug/TXA Administration | IL-1β | 20.7 pg/ml |
| TXA127 | Cytokine Levels on the Day of Drug/TXA Administration | IL-1Ra | 15.9 pg/ml |
| TXA127 | Cytokine Levels on the Day of Drug/TXA Administration | IL-2 | 0.52 pg/ml |
| TXA127 | Cytokine Levels on the Day of Drug/TXA Administration | IL-4 | 0.41 pg/ml |
| TXA127 | Cytokine Levels on the Day of Drug/TXA Administration | IL-5 | 1.72 pg/ml |
| TXA127 | Cytokine Levels on the Day of Drug/TXA Administration | IL-6 | 9.63 pg/ml |
| TXA127 | Cytokine Levels on the Day of Drug/TXA Administration | IL-8 | 24.4 pg/ml |
| TXA127 | Cytokine Levels on the Day of Drug/TXA Administration | TNF-α | 68.4 pg/ml |
| TXA127 | Cytokine Levels on the Day of Drug/TXA Administration | IL-10 | 12.3 pg/ml |
| TXA127 | Cytokine Levels on the Day of Drug/TXA Administration | IL-12p40 | 32.4 pg/ml |
| TXA127 | Cytokine Levels on the Day of Drug/TXA Administration | IL-12p70 | 1.74 pg/ml |
| TXA127 | Cytokine Levels on the Day of Drug/TXA Administration | IL-13 | 9.9 pg/ml |
| Placebo | Cytokine Levels on the Day of Drug/TXA Administration | IL-10 | 10.8 pg/ml |
| Placebo | Cytokine Levels on the Day of Drug/TXA Administration | MCP-1 | 283 pg/ml |
| Placebo | Cytokine Levels on the Day of Drug/TXA Administration | IL-6 | 3.35 pg/ml |
| Placebo | Cytokine Levels on the Day of Drug/TXA Administration | Interferon-γ | 1.0 pg/ml |
| Placebo | Cytokine Levels on the Day of Drug/TXA Administration | IL-12p70 | 0.63 pg/ml |
| Placebo | Cytokine Levels on the Day of Drug/TXA Administration | IL-1β | 30.6 pg/ml |
| Placebo | Cytokine Levels on the Day of Drug/TXA Administration | IL-8 | 16.2 pg/ml |
| Placebo | Cytokine Levels on the Day of Drug/TXA Administration | IL-1Ra | 7.6 pg/ml |
| Placebo | Cytokine Levels on the Day of Drug/TXA Administration | IL-12p40 | 28.9 pg/ml |
| Placebo | Cytokine Levels on the Day of Drug/TXA Administration | IL-2 | 0.37 pg/ml |
| Placebo | Cytokine Levels on the Day of Drug/TXA Administration | TNF-α | 45.9 pg/ml |
| Placebo | Cytokine Levels on the Day of Drug/TXA Administration | IL-4 | 0.21 pg/ml |
| Placebo | Cytokine Levels on the Day of Drug/TXA Administration | IL-13 | 8.5 pg/ml |
| Placebo | Cytokine Levels on the Day of Drug/TXA Administration | IL-5 | 1.21 pg/ml |
Secondary
Days of Hospital Stay and Drug Administration
Time frame: Day 1 to Day 10
Population: Only subjects who received at least 1 complete dose of drug/placebo were included in the data analysis. This included 11 out of 11 in the TXA127 group and 9 out of 11 in the Placebo group.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| TXA127 | Days of Hospital Stay and Drug Administration | Length of Hospital Stay | 11 days |
| TXA127 | Days of Hospital Stay and Drug Administration | Days of Drug/placebo administration | 4 days |
| Placebo | Days of Hospital Stay and Drug Administration | Length of Hospital Stay | 7 days |
| Placebo | Days of Hospital Stay and Drug Administration | Days of Drug/placebo administration | 5 days |
Secondary
Mortality
Time frame: Day 1 to Day 10
Population: Only subjects who received at least 1 complete dose of drug/placebo were included in the data analysis. This included 11 out of 11 in the TXA127 group and 9 out of 11 in the Placebo group.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| TXA127 | Mortality | 1 Participants |
| Placebo | Mortality | 0 Participants |
Secondary
Number of Participants Requiring a Vasopressors
Time frame: Up to Day 10
Population: Only subjects who received at least 1 complete dose of drug/placebo were included in the data analysis. This included 11 out of 11 in the TXA127 group and 9 out of 11 in the Placebo group.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| TXA127 | Number of Participants Requiring a Vasopressors | 3 Participants |
| Placebo | Number of Participants Requiring a Vasopressors | 1 Participants |
Secondary
Number of Participants Requiring Dialysis
Time frame: Up to Day 10
Population: Only subjects who received at least 1 complete dose of drug/placebo were included in the data analysis. This included 11 out of 11 in the TXA127 group and 9 out of 11 in the Placebo group.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| TXA127 | Number of Participants Requiring Dialysis | 0 Participants |
| Placebo | Number of Participants Requiring Dialysis | 0 Participants |
Secondary
Percent Change in Supplemental Oxygen Requirements
Time frame: Day 1 and Day 10
Population: Only subjects who received at least 1 complete dose of drug/placebo were included in the data analysis. This included 11 out of 11 in the TXA127 group and 9 out of 11 in the Placebo group.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| TXA127 | Percent Change in Supplemental Oxygen Requirements | 0.71 percent change of oxygen |
| Placebo | Percent Change in Supplemental Oxygen Requirements | 0.91 percent change of oxygen |