Acute Kidney Injury, Septic Shock
Conditions
Keywords
Renin, Angiotensin II, vasopressor, sepsis
Brief summary
Septic shock continues to exert a large economic burden around the world. Several developments have occurred that lead to the current study. First, angiotensin II is the newest FDA approved vasopressor agent indicated for use in vasodilatory shock. Several subgroups from the approval trial have indicated that angiotensin II may confer a survival benefit in certain conditions, including those patients requiring continuous renal replacement therapy, those with altered angiotensin I: angiotensin II ratios, and most recently, those with elevated renin levels (which may serve as a surrogate for dysfunctional angiotensin 1: angiotensin II ratios). This open-label, sequential period pilot study will evaluate angiotensin II and biomarker response (renin) in the treatment of septic shock.
Interventions
OTHERStandard of Care
These patients will receive standard of care treatment. Plasma renin levels and biomarkers of renal function will be measured.
DRUGAngiotensin II
These patients will receive angiotensin II in addition to standard of care treatment. Plasma renin levels and biomarkers of renal function will be measured.
Sponsors
Alexander Flannery
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Medical ICU admission * Septic shock * Norepinephrine requirement = 0.15 mcg/kg/min for = 30 minutes (if cirrhosis, norepinephrine requirement = 0.1 mcg/kg/min for = 30 minutes) * Kidney Disease Improving Global Outcomes stage 1 or greater Acute Kidney Injury
Exclusion criteria
* Prisoner * Pregnancy * Acute occlusive coronary syndrome requiring intervention or acute myocardial infarction of any degree * Purely cardiogenic shock (no distributive component) * Mesenteric ischemia * Acute ischemic stroke * Hemorrhagic shock * Active treatment of hepatorenal syndrome targeting a Mean Arterial Pressure = 65 mm Hg * Planned withdrawal of care within next 24 hours or no escalation of care * Patient enrolled in an interventional study * High likelihood of medical futility in using this drug: * 3 or more vasopressors required to sustain MAP * Sustained norepinephrine equivalents \> 0.5 mcg/kg/min * COVID-19 positive, or high suspicion of COVID-19
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Plasma Renin Levels | Until shock resolution, up to 14 days (at baseline, 3 hours, 24 hours, and shock resolution, up to 14 days) | Plasma renin levels will be measured from blood collected at baseline, 24 hours, and at shock resolution. Additionally, a 3-hour measurement will be included in the angiotensin II arm. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Days to Discontinuation of Catecholamines | Until shock resolution, up to 14 days | Days from enrollment to discontinuation of catecholamines |
| ICU Length of Stay | From enrollment to ICU discharge, up to 28 days following enrollment | Number of days in the intensive care unit (ICU). |
| Number of Participants With In-hospital Mortality | Up to 3 months following enrollment | Assessment of all-cause mortality within hospital admission |
| Change in Plasma Cystatin C | Until shock resolution, up to 14 days (at baseline, 3 hours, 24 hours, and shock resolution, up to 14 days) | Cystatin C will be measured from blood collected at baseline, 24 hours, and at shock resolution. |
| Number of Participants Experiencing Prespecified Safety Outcomes | Up to 72 hours following shock resolution, no longer than 17 days from enrollment | Incidence of venous thromboembolism, arrhythmia, extremity hypoperfusion, delirium, new ischemic event, new infection |
| Change in Plasma Neutrophil Gelatinase-associated Lipocalin (NGAL) | Until shock resolution, up to 14 days (at baseline, 3 hours, 24 hours, and shock resolution, up to 14 days) | NGAL will be measured from blood collected at baseline, 24 hours, and at shock resolution. |
| Renal Replacement Therapy-free Days | Within 28 days of enrollment | Days free of renal replacement therapy from enrollment up to day 28 |
Countries
United States
Participant flow
Pre-assignment details
2 enrolled participants in the angiotensin II arm had changes in status that deemed them ineligible for the study and they subsequently did not receive open label angiotensin II.
Participants by arm
| Arm | Count |
|---|---|
| Standard of Care Cohort Patients in this group will receive standard of care treatment.
Standard of Care: These patients will receive standard of care treatment. Plasma renin levels and biomarkers of renal function will be measured. | 10 |
| Angiotensin II Cohort Patients in this group will receive angiotensin II.
Angiotensin II: These patients will receive angiotensin II in addition to standard of care treatment. Plasma renin levels and biomarkers of renal function will be measured. | 18 |
| Total | 28 |
Baseline characteristics
| Characteristic | Standard of Care Cohort | Total | Angiotensin II Cohort |
|---|---|---|---|
| Age, Continuous | 63 years | 62 years | 61 years |
| 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 | 1 Participants | 3 Participants | 2 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 | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 9 Participants | 25 Participants | 16 Participants |
| Region of Enrollment United States | 10 participants | 28 participants | 18 participants |
| Sex: Female, Male Female | 5 Participants | 12 Participants | 7 Participants |
| Sex: Female, Male Male | 5 Participants | 16 Participants | 11 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 9 / 10 | 9 / 18 |
| other Total, other adverse events | 0 / 10 | 0 / 18 |
| serious Total, serious adverse events | 0 / 10 | 0 / 18 |
Outcome results
Primary
Change in Plasma Renin Levels
Plasma renin levels will be measured from blood collected at baseline, 24 hours, and at shock resolution. Additionally, a 3-hour measurement will be included in the angiotensin II arm.
Time frame: Until shock resolution, up to 14 days (at baseline, 3 hours, 24 hours, and shock resolution, up to 14 days)
Population: Number analyzed in one or more rows may be different from overall number due to participant death which would preclude subsequent measurements. 3-hour sample was only done in the angiotensin II arm.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Standard of Care Cohort | Change in Plasma Renin Levels | Baseline Minus 24-Hour Sample | -15 pg/mL |
| Standard of Care Cohort | Change in Plasma Renin Levels | Baseline Minus Shock Resolution | -6 pg/mL |
| Angiotensin II Cohort | Change in Plasma Renin Levels | Baseline Minus 24-Hour Sample | 69 pg/mL |
| Angiotensin II Cohort | Change in Plasma Renin Levels | Baseline Minus Shock Resolution | 26 pg/mL |
| Angiotensin II Cohort | Change in Plasma Renin Levels | Baseline Minus 3-Hour | 41 pg/mL |
Secondary
Change in Plasma Cystatin C
Cystatin C will be measured from blood collected at baseline, 24 hours, and at shock resolution.
Time frame: Until shock resolution, up to 14 days (at baseline, 3 hours, 24 hours, and shock resolution, up to 14 days)
Population: Number analyzed in one or more rows may be different from overall number due to participant death which would preclude subsequent measurements. 3-hour sample was done only in the angiotensin II arm.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Standard of Care Cohort | Change in Plasma Cystatin C | Baseline Minus 24-Hour | -254 ng/mL |
| Standard of Care Cohort | Change in Plasma Cystatin C | Baseline Minus Shock Resolution | 99 ng/mL |
| Angiotensin II Cohort | Change in Plasma Cystatin C | Baseline Minus 24-Hour | -143 ng/mL |
| Angiotensin II Cohort | Change in Plasma Cystatin C | Baseline Minus Shock Resolution | -124 ng/mL |
| Angiotensin II Cohort | Change in Plasma Cystatin C | Baseline Minus 3-Hour | -196 ng/mL |
Secondary
Change in Plasma Neutrophil Gelatinase-associated Lipocalin (NGAL)
NGAL will be measured from blood collected at baseline, 24 hours, and at shock resolution.
Time frame: Until shock resolution, up to 14 days (at baseline, 3 hours, 24 hours, and shock resolution, up to 14 days)
Population: Number analyzed in one or more rows may be different from overall number due to participant death which would preclude subsequent measurements. 3-hour sample was only done in the angiotensin II arm.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Standard of Care Cohort | Change in Plasma Neutrophil Gelatinase-associated Lipocalin (NGAL) | Baseline Minus 24-Hour | 10 ng/mL |
| Standard of Care Cohort | Change in Plasma Neutrophil Gelatinase-associated Lipocalin (NGAL) | Baseline Minus Shock Resolution | 18 ng/mL |
| Angiotensin II Cohort | Change in Plasma Neutrophil Gelatinase-associated Lipocalin (NGAL) | Baseline Minus 24-Hour | 93 ng/mL |
| Angiotensin II Cohort | Change in Plasma Neutrophil Gelatinase-associated Lipocalin (NGAL) | Baseline Minus Shock Resolution | 201 ng/mL |
| Angiotensin II Cohort | Change in Plasma Neutrophil Gelatinase-associated Lipocalin (NGAL) | Baseline Minus 3-Hour | -21 ng/mL |
Secondary
Days to Discontinuation of Catecholamines
Days from enrollment to discontinuation of catecholamines
Time frame: Until shock resolution, up to 14 days
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Standard of Care Cohort | Days to Discontinuation of Catecholamines | 0.9 days |
| Angiotensin II Cohort | Days to Discontinuation of Catecholamines | 3.5 days |
Secondary
ICU Length of Stay
Number of days in the intensive care unit (ICU).
Time frame: From enrollment to ICU discharge, up to 28 days following enrollment
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Standard of Care Cohort | ICU Length of Stay | 4.3 days |
| Angiotensin II Cohort | ICU Length of Stay | 7.2 days |
Secondary
Number of Participants Experiencing Prespecified Safety Outcomes
Incidence of venous thromboembolism, arrhythmia, extremity hypoperfusion, delirium, new ischemic event, new infection
Time frame: Up to 72 hours following shock resolution, no longer than 17 days from enrollment
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Standard of Care Cohort | Number of Participants Experiencing Prespecified Safety Outcomes | 0 Participants |
| Angiotensin II Cohort | Number of Participants Experiencing Prespecified Safety Outcomes | 0 Participants |
Secondary
Number of Participants With In-hospital Mortality
Assessment of all-cause mortality within hospital admission
Time frame: Up to 3 months following enrollment
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Standard of Care Cohort | Number of Participants With In-hospital Mortality | 9 Participants |
| Angiotensin II Cohort | Number of Participants With In-hospital Mortality | 9 Participants |
Secondary
Renal Replacement Therapy-free Days
Days free of renal replacement therapy from enrollment up to day 28
Time frame: Within 28 days of enrollment
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Standard of Care Cohort | Renal Replacement Therapy-free Days | 0 days |
| Angiotensin II Cohort | Renal Replacement Therapy-free Days | 21 days |