Acute Infection, Organ Failure, Sepsis
Conditions
Brief summary
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.
Interventions
DRUGFisetin-dose 1
20mg/kg once a day for one day.
DRUGFisetin-dose 2
20mg/kg once a day for two days
DRUGPlacebo
Placebo treatment
Sponsors
University of Minnesota
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Intervention model description
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.
Eligibility
Sex/Gender
ALL
Age
65 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Age \>=65 years * Primary diagnosis of acute infection (per investigator judgment) * SOFA \>1 * Admission order to the hospital * Expected length of stay \>=48 hours (per investigator judgment)
Exclusion criteria
* Admission to the ICU * Vasopressors, mechanical ventilation, or dialysis * Comfort care only * Total bilirubin \>3X or AST/ALT \>4x upper limit of normal * eGFR \< 25 ml/ min/ 1.73 m2 * Hemoglobin \<7 g/dL; white blood cell count ≤ 2,000/mm3; absolute neutrophil count ≤1 x 10\^9/;, or platelet count ≤ 40,000/μL * Known HIV, Hepatitis B, or Hepatitis C * Invasive fungal infection (per investigator judgment) * Uncontrolled effusions or ascites (per investigator judgment) * New/active invasive cancer except non-melanoma skin cancers * Known hypersensitivity or allergy to Fisetin. * Active treatment with potential drug-drug interactions * Enrolled in another sepsis clinical trial
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Difference in the composite cardiovascular, respiratory, and renal sequential organ failure assessment (CRR-SOFA) | day 7 | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Safety of 2 doses of fisetin in patients with mild sepsis | day 28 | Outcome is the number of serious adverse event |
| Organ failure free days | day 28 | 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. |
| Total SOFA score | day 7 | 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. |
| Zubrod performance status | day 7 | 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. |
| SF-12 score | day 7 | 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. |
| Days in the ICU | day 28 | This outcome is the number of days the patient was admitted to the ICU. |
| All-cause mortality | Day 28 | This outcome is the proportion of patients suffering all-cause mortality prior to day 28. |
| Peripheral CD3+ senescent (SnCs) immune 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 | Outcome is the relative expression of p16Ink4a in CD3+ cells. |
| TNF-alpha | day 7 | Outcome is the concentration of TNF-alpha by Luminex human discovery assay |
Countries
United States
Contacts
CONTACTMichael Puskarich, MD
PRINCIPAL_INVESTIGATORMichael Puskarich, MD
University of Minnesota
Outcome results
None listed