Inflammation and Stem Cells in Diabetic and Chronic Kidney Disease

Study Overview
=================
Brief Summary
-----------------
The proposed studies will examine the effect of fisetin on adipose tissue-derived mesenchymal stem/stromal cell function, kidney function, markers of inflammation, and physical function in individuals with advanced chronic kidney disease.

Detailed Description
-----------------
The proposed studies will examine the effect of fisetin on adipose tissue-derived mesenchymal stem/stromal cell function, kidney function, markers of inflammation, and physical function in individuals with advanced chronic kidney disease, particularly diabetic kidney disease. This study will involve a single 2-day oral treatment regimen with fisetin or placebo. Study subjects will be randomized 2:1 to study drug or placebo. Study visits will consist of blood, urine, and abdominal wall skin and subcutaneous fat samplings in addition to testing of physical strength at given time points. Subjects will be followed for a total of 12 months.

Official Title
-----------------
Frailty, Inflammation, and Stem Cell Functionality in Chronic Kidney Disease

Conditions
-----------------
Chronic Kidney Diseases, Diabetes Mellitus, Diabetic Nephropathies

Intervention / Treatment
-----------------
* Dietary Supplement: Fisetin
* Drug: Placebo oral capsule


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Age 40-80 years Chronic kidney disease estimated glomerular filtration rate (eGFR) 15-60 ml/min/1.73m2 For the diabetic kidney disease (DKD) subgroup: Diabetes mellitus (on medication) Exclusion Criteria: Hemoglobin A1c>11% at screening for the DKD subgroup Body weight >150 kg or body mass index>50 Pregnancy Active glomerulonephritis treated with immunosuppressive therapy Solid organ transplantation (eg. kidney, pancreas, liver, lung, heart) Active immunosuppression therapy History of active substance abuse (including alcohol) within the past 2 years, Current alcohol abuse (>3 alcoholic beverages/day or >21 per week), Human immunodeficiency virus infection Active hepatitis B or C infection Total bilirubin >2x upper limit of normal Uncontrolled psychiatric disorder Uncontrolled systemic lupus erythematosus Uncontrolled pleural/pericardial effusions or ascites New invasive cancer except non-melanoma skin cancers Invasive fungal or viral infection Inability to tolerate oral medications Known hypersensitivity or allergy to Fisetin Subjects taking medications that are sensitive to substrates or substrates with a narrow therapeutic range for CYP3A4, CYP2C8, CYP2C9, or CYP2D6CYP2C9, CYP2C19, CYP1A2, Other (OATP1B1) (Unless willing and able to stop or modify the dosing of the drug) or strong inhibitors or inducers of CYP3A4 (e.g. cyclosporine, tacrolimus or sirolimus). Tyrosine kinase inhibitor therapy Subjects on therapeutic doses of anticoagulants (e.g., warfarin, heparin, low molecular weight heparin, factor Xa inhibitors, etc.). Subjects on full-dose 325 mg aspirin or other anti-platelet agents (eg. clopidogrel) daily who are unable or unwilling to reduce or hold therapy prior to and during the 2-day drug dosing. Subjects may continue their previous regimen on day 3. Baby aspirin (81 mg), if necessary for cardioprotection, will be allowed but encouraged to hold. Subjects taking proton pump inhibitors who are unable or unwilling to reduce or hold therapy 2 days prior to and during the 2-day drug dosing. Subjects taking H2-antagonists and unwilling to discontinue therapy for 2 weeks before and one week following enrollment. (See Appendix 4) Subjects taking glimepiride or glyburide for diabetes therapy who are unable or unwilling to reduce or hold therapy prior to and during the 2-day drug dosing. Subjects taking the following antimicrobial agents: Aminoglycosides, Azole antifungals (fluconazole, miconazole, voriconazole, itraconazole), Macrolides (clarithromycin, erythromycin), Antivirals (nelfinavir, indinavir, saquinavir, ritonavir, elbasvir/grazoprevir), Rifampin Corrected QT interval (QTc) >450 msec Tobacco use (smoking or chewing; Unless subject willing to reduce use by 50% prior to and during the study) - see Behavioral Modification information below. Inability to give informed consent Presence of any condition that the Investigator believes would put the subject at risk or would preclude the patient from successfully completing all aspects of the trial

Ages Eligible for Study
-----------------
Minimum Age: 40 Years
Maximum Age: 80 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
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment<br>Fisetin 20 mg/kg/day, orally for 2 consecutive days | Dietary Supplement: Fisetin<br>* Flavonoid family<br>|
| Placebo Comparator: Placebo<br>Placebo capsules orally for 2 consecutive days | Drug: Placebo oral capsule<br>* Placebo<br>* Other names: Placebo;|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in inflammatory markers including C-reactive protein | To examine the effect of study drug (compared to placebo) on markers of inflammation in skin, fat, plasma, and urine measured at baseline and day 14 | 14 days | 
| Effect on Mesenchymal stem cell function including cell migration | To examine the effect of study drug (compared to placebo) on mesenchymal stem cell function and vitality measured at baseline and day 14 | 14 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Effect on measures of Frailty including Fried Criteria | To examine the effect of study drug (compared to placebo) on markers of physical frailty (frailty phenotype). | 4 months | 
| Kidney function including estimated glomerular filtration rate | To examine the effect of study drug (compared to placebo) on kidney function. | 4 months | 
| Kidney function including urine protein excretion rate | To examine the effect of study drug (compared to placebo) on kidney function protein excretion | 4 months | 
| Number of participants with treatment-related adverse events including hospitalization | To assess the safety and tolerability of study drug taken over two days (compared to placebo) | 12 months | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Frailty, Inflammation, Mesenchymal stem cell, Mesenchymal stromal cell