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The long-term goal is to test the clinical efficacy of senolytic therapies to reduce progression to and severity of sepsis in older patients. The central hypothesis is that a threshold burden of SnCs predisposes to a SASP mediated dysfunctional response to PAMPs, contributing to a disproportionate burden of sepsis in older patients. The study hypothesizes timely treatment with fisetin will interrupt this pathway.
A multicenter, randomized, adaptive allocation clinical trial to identify the most efficacious dose of the senolytic fisetin to reduce the composite cardiovascular, respiratory, and renal sequential organ failure assessment score at 1 week, and predict the probability of success of a definitive phase III clinical trial.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Fisetin- dose 1 | Experimental | Elderly (>=65 years) patients admitted to the hospital with an acute infection and sequential organ failure assessment score sufficient for a diagnosis of sepsis, will be given the first dose of fisetin. |
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| Fisetin- dose 2 | Experimental | Elderly (>=65 years) patients admitted to the hospital with an acute infection and sequential organ failure assessment score sufficient for a diagnosis of sepsis, will be given the 2nd does of fisetin. |
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| Placebo | Placebo Comparator | Elderly (>=65 years) patients admitted to the hospital with an acute infection and sequential organ failure assessment score sufficient for a diagnosis of sepsis will receive placebo treatment. |
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Fisetin-dose 1 | Drug | 20mg/kg once a day for one day. |
| |
| Measure | Description | Time Frame |
|---|---|---|
| Difference in the composite cardiovascular, respiratory, and renal sequential organ failure assessment (CRR-SOFA) | The Sequential Organ Failure Assessment (SOFA) score is a scoring system that assesses the performance of several organ systems in the body (neurologic, blood, liver, kidney, and blood pressure/hemodynamics) and assigns a score based on the data obtained in each category. This outcome assesses only the cardiovascular, respiratory, and renal categories of the total SOFA score, and calculates the change from day 0 to day 7. | day 7 |
| Measure | Description | Time Frame |
|---|---|---|
| Safety of 2 doses of fisetin in patients with mild sepsis | Outcome is the number of serious adverse event | day 28 |
| Organ failure free days | Outcome is 28 days minus the last day the patient required any of the following: ventilator support, vasopressors, or dialysis / renal replacement therapy. Patients who die prior to day 28 are given a value of -1. |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| Michael Puskarich, MD | Contact | 612 626 6911 | mike-em@umn.edu |
| Name | Affiliation | Role |
|---|---|---|
| Michael Puskarich, MD | University of Minnesota | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| University of Florida | Recruiting | Gainesville | Florida | 32608 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 39434114 | Derived | Silva M, Wacker DA, Driver BE, Staugaitis A, Niedernhofer LJ, Schmidt EL, Kirkland JL, Tchkonia T, Evans T, Serrano CH, Ventz S, Koopmeiners JS, Puskarich MA; STOP-Sepsis Investigators. Senolytics To slOw Progression of Sepsis (STOP-Sepsis) in elderly patients: Study protocol for a multicenter, randomized, adaptive allocation clinical trial. Trials. 2024 Oct 21;25(1):698. doi: 10.1186/s13063-024-08474-2. |
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Participants will initially be equally randomized between placebo, 20 mg/kg (once), and 20 mg/kg (once daily for 2 days). After 60 participants have been enrolled, the randomization ratio will be adapted so that a higher proportion of participants will be randomized to the optimal dosing regimen. The proportion randomized to the control will be held constant throughout the trial.
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| Fisetin-dose 2 |
| Drug |
20mg/kg once a day for two days |
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| Placebo | Drug | Placebo treatment |
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| day 28 |
| Total SOFA score | The Sequential Organ Failure Assessment (SOFA) score is a scoring system that assesses the performance of several organ systems in the body (neurologic, blood, liver, kidney, and blood pressure/hemodynamics) and assigns a score based on the data obtained in each category. | day 7 |
| Zubrod performance status | A scale for indicating a patient's functional level: 0 asymptomatic - 1 Symptomatic, fully ambulatory - 2 Symptomatic, in bed - 50% of the day - 3 Symptomatic, in bed; 50% of the day but not bedridden - 4 Bedridden - 5 Dead. | day 7 |
| SF-12 score | The SF-12 is a self-reported validated outcome measure assessing the impact of health on an individual 39;s everyday life. Patients fill out a 12 question survey which is then scored by a clinician or researcher. | day 7 |
| SF-12 score | The SF-12 is a self-reported validated outcome measure assessing the impact of health on an individual 39;s everyday life. Patients fill out a 12 question survey which is then scored by a clinician or researcher. | day 28 |
| Zubrod performance status | A scale for indicating a patient's functional level: 0 asymptomatic - 1 Symptomatic, fully ambulatory - 2 Symptomatic, in bed - 50% of the day - 3 Symptomatic, in bed; 50% of the day but not bedridden - 4 Bedridden - 5 Dead. | day 28 |
| Days in the ICU | This outcome is the number of days the patient was admitted to the ICU. | day 28 |
| All-cause mortality | This outcome is the proportion of patients suffering all-cause mortality prior to day 28. | Day 28 |
| Peripheral CD3+ senescent (SnCs) immune cells | Outcome is the relative expression of p16Ink4a in CD3+ cells. | day 7 |
| Outcome is the relative expression of p16Ink4a in CD3+ cells. | Outcome is the relative expression of p16Ink4a in CD3+ cells. | day 28 |
| TNF-alpha | Outcome is the concentration of TNF-alpha by Luminex human discovery assay | day 7 |
| University of Iowa | Recruiting | Iowa City | Iowa | 52242 | United States |
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| Ridges | Recruiting | Burnsville | Minnesota | 55337 | United States |
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| Southdale | Recruiting | Edina | Minnesota | 55435 | United States |
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| M Health Fairview St. John's | Recruiting | Maplewood | Minnesota | 55109 | United States |
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| St. John's | Recruiting | Maplewood | Minnesota | 55109 | United States |
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| University of Minnesota | Recruiting | Minneapolis | Minnesota | 55414 | United States |
| HCMC | Recruiting | Minneapolis | Minnesota | 55415 | United States |
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| UMMC | Recruiting | Minneapolis | Minnesota | 55455 | United States |
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| University of Mississippi Medical Center | Recruiting | Jackson | Mississippi | 39216 | United States |
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| ID | Term |
|---|---|
| D018805 | Sepsis |
| ID | Term |
|---|---|
| D007239 | Infections |
| D018746 | Systemic Inflammatory Response Syndrome |
| D007249 | Inflammation |
| D010335 | Pathologic Processes |
| D013568 | Pathological Conditions, Signs and Symptoms |
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