Senolytics To slOw Progression of Sepsis (STOP-Sepsis) Trial

Study Overview
=================
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.

Official Title
-----------------
Senolytics To slOw Progression of Sepsis (STOP-Sepsis) Trial

Conditions
-----------------
Sepsis, Acute Infection, Organ Failure

Intervention / Treatment
-----------------
* Drug: Fisetin-dose 1
* Drug: Fisetin-dose 2
* Drug: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
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

Ages Eligible for Study
-----------------
Minimum Age: 65 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional 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.
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Fisetin- dose 1<br>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. | Drug: Fisetin-dose 1<br>* 20mg/kg once a day for one day.<br>|
| Experimental: Fisetin- dose 2<br>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. | Drug: Fisetin-dose 2<br>* 20mg/kg once a day for two days<br>|
| Placebo Comparator: Placebo<br>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. | Drug: Placebo<br>* Placebo treatment<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | 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 | 

Secondary Outcome Measures

| Outcome Measure | 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. | 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 |