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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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Standard of Care Cohort | Active Comparator | Patients in this group will receive standard of care treatment. |
|
| Angiotensin II Cohort | Experimental | Patients in this group will receive angiotensin II. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Standard of Care | Other | These patients will receive standard of care treatment. Plasma renin levels and biomarkers of renal function will be measured. |
|
| Measure | Description | Time Frame |
|---|---|---|
| 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. | Until shock resolution, up to 14 days (at baseline, 3 hours, 24 hours, and shock resolution, up to 14 days) |
| Measure | Description | Time Frame |
|---|---|---|
| Change in Plasma Cystatin C | Cystatin C will be measured from blood collected at baseline, 24 hours, and at shock resolution. | Until shock resolution, up to 14 days (at baseline, 3 hours, 24 hours, and shock resolution, up to 14 days) |
| Days to Discontinuation of Catecholamines |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Alexander H Flannery, Pharm.D. | University of Kentucky | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| University of Kentucky HealthCare Chandler Medical Center | Lexington | Kentucky | 40536 | United States |
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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.
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| ID | Title | Description |
|---|---|---|
| FG000 | 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. |
| FG001 | 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. |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
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| ID | Title | Description |
|---|---|---|
| BG000 | 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. |
| BG001 | Angiotensin II Cohort |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Median |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 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. | 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. | Posted | Median | Inter-Quartile Range | pg/mL | Until shock resolution, up to 14 days (at baseline, 3 hours, 24 hours, and shock resolution, up to 14 days) |
|
Up to 72 hours following shock resolution, no longer than 17 days from enrollment
Targeted screening for venous thromboembolism, arrhythmia, extremity hypoperfusion, delirium, new ischemic event, new infection from enrollment up to 72 hours following shock resolution.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | 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. |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Alexander Flannery, PharmD, PhD | University of Kentucky | 859-562-2766 | alexander.flannery@gmail.com |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Mar 19, 2020 | Jul 23, 2024 | Prot_SAP_000.pdf |
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| ID | Term |
|---|---|
| D012772 | Shock, Septic |
| D058186 | Acute Kidney Injury |
| D018805 | Sepsis |
| ID | Term |
|---|---|
| D007239 | Infections |
| D018746 | Systemic Inflammatory Response Syndrome |
| D007249 | Inflammation |
| D010335 | Pathologic Processes |
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| ID | Term |
|---|---|
| D059039 | Standard of Care |
| D000804 | Angiotensin II |
| ID | Term |
|---|---|
| D019984 | Quality Indicators, Health Care |
| D011787 | Quality of Health Care |
| D006298 | Health Services Administration |
| D017530 | Health Care Quality, Access, and Evaluation |
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| Angiotensin II | Drug | These patients will receive angiotensin II in addition to standard of care treatment. Plasma renin levels and biomarkers of renal function will be measured. |
|
Days from enrollment to discontinuation of catecholamines |
| Until shock resolution, up to 14 days |
| ICU Length of Stay | Number of days in the intensive care unit (ICU). | From enrollment to ICU discharge, up to 28 days following enrollment |
| Number of Participants With In-hospital Mortality | Assessment of all-cause mortality within hospital admission | Up to 3 months following enrollment |
| Renal Replacement Therapy-free Days | Days free of renal replacement therapy from enrollment up to day 28 | Within 28 days of enrollment |
| Number of Participants Experiencing Prespecified Safety Outcomes | Incidence of venous thromboembolism, arrhythmia, extremity hypoperfusion, delirium, new ischemic event, new infection | Up to 72 hours following shock resolution, no longer than 17 days from enrollment |
| Change in Plasma Neutrophil Gelatinase-associated Lipocalin (NGAL) | NGAL will be measured from blood collected at baseline, 24 hours, and at shock resolution. | Until shock resolution, up to 14 days (at baseline, 3 hours, 24 hours, and shock resolution, up to 14 days) |
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. |
| BG002 | Total | Total of all reporting groups |
| years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Race (NIH/OMB) | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
| OG001 |
| 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. |
|
|
| Secondary | Change in Plasma Cystatin C | Cystatin C will be measured from blood collected at baseline, 24 hours, and at shock resolution. | 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. | Posted | Median | Inter-Quartile Range | ng/mL | Until shock resolution, up to 14 days (at baseline, 3 hours, 24 hours, and shock resolution, up to 14 days) |
|
|
|
| Secondary | Days to Discontinuation of Catecholamines | Days from enrollment to discontinuation of catecholamines | Posted | Median | Inter-Quartile Range | days | Until shock resolution, up to 14 days |
|
|
|
| Secondary | ICU Length of Stay | Number of days in the intensive care unit (ICU). | Posted | Median | Inter-Quartile Range | days | From enrollment to ICU discharge, up to 28 days following enrollment |
|
|
|
| Secondary | Number of Participants With In-hospital Mortality | Assessment of all-cause mortality within hospital admission | Posted | Count of Participants | Participants | Up to 3 months following enrollment |
|
|
|
| Secondary | Renal Replacement Therapy-free Days | Days free of renal replacement therapy from enrollment up to day 28 | Posted | Median | Inter-Quartile Range | days | Within 28 days of enrollment |
|
|
|
| Secondary | Number of Participants Experiencing Prespecified Safety Outcomes | Incidence of venous thromboembolism, arrhythmia, extremity hypoperfusion, delirium, new ischemic event, new infection | Posted | Count of Participants | Participants | Up to 72 hours following shock resolution, no longer than 17 days from enrollment |
|
|
|
| Secondary | Change in Plasma Neutrophil Gelatinase-associated Lipocalin (NGAL) | NGAL will be measured from blood collected at baseline, 24 hours, and at shock resolution. | 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. | Posted | Median | Inter-Quartile Range | ng/mL | Until shock resolution, up to 14 days (at baseline, 3 hours, 24 hours, and shock resolution, up to 14 days) |
|
|
|
| 9 |
| 10 |
| 0 |
| 10 |
| 0 |
| 10 |
| EG001 | 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. | 9 | 18 | 0 | 18 | 0 | 18 |
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| D013568 |
| Pathological Conditions, Signs and Symptoms |
| D012769 | Shock |
| D051437 | Renal Insufficiency |
| D007674 | Kidney Diseases |
| D014570 | Urologic Diseases |
| D052776 | Female Urogenital Diseases |
| D005261 | Female Urogenital Diseases and Pregnancy Complications |
| D000091642 | Urogenital Diseases |
| D052801 | Male Urogenital Diseases |
| D000809 | Angiotensins |
| D036361 | Peptide Hormones |
| D006728 | Hormones |
| D006730 | Hormones, Hormone Substitutes, and Hormone Antagonists |
| D009479 | Neuropeptides |
| D010455 | Peptides |
| D000602 | Amino Acids, Peptides, and Proteins |
| D009842 | Oligopeptides |
| D009419 | Nerve Tissue Proteins |
| D011506 | Proteins |
| D012898 | Autacoids |
| D018836 | Inflammation Mediators |
| D001685 | Biological Factors |
| Baseline Minus Shock Resolution |
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| Baseline Minus 3-Hour |
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| Baseline Minus Shock Resolution |
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| Baseline Minus 3-Hour |
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