Senescence in Chronic Kidney Disease

Senescence, Frailty, and Mesenchymal Stem Cell Functionality in Chronic Kidney Disease: Effect of Senolytic Agents

The study goal is to assess the effect of senescent cell clearance on senescence burden, physical ability or frailty, and adipose tissue-derived mesenchymal stem cell (MSC) functionality in patients with chronic kidney disease (CKD).

Study Overview

• Status: Enrolling by invitation
• Conditions: Chronic Kidney Disease
• Intervention / Treatment: Drug: Group 2: Dasatinib; Drug: Group 2: Quercetin

Detailed Description

The proposed studies will examine cellular senescence and the effect of senolytic therapy on senescent cell burden, frailty, and adipose-derived mesenchymal stem cell function in individuals with diabetic chronic kidney disease.

• Study Type: Interventional
• Enrollment (Estimated): 30
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Florida
    • Jacksonville, Florida, United States, 32224
      • Mayo Clinic Florida
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic in Rochester

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 40 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Age 40-80 years
2. Chronic kidney disease estimated glomerular filtration rate (eGFR) 15-45 ml/min/1.73m2
3. Diabetes mellitus and taking diabetes medications

Exclusion Criteria:

1. Concomitant glomerulonephritis,
2. Nephrotic syndrome,
3. Solid organ transplantation,
4. Autosomal dominant or recessive polycystic kidney disease,
5. Known renovascular disease,
6. Pregnancy,
7. Active immunosuppression therapy,
8. Hemoglobin A1c≥10% at screening,
9. History of active substance abuse (including alcohol) within the past 2 years,
10. Current alcohol abuse (>3 alcoholic beverages/day or >21 per week),
11. Body weight >150 kg or body mass index>50
12. Human immunodeficiency virus infection
13. Active hepatitis B or C infection
14. Tyrosine kinase inhibitor therapy
15. Known hypersensitivity or allergy to dasatinib or quercetin
16. Inability to give informed consent
17. Uncontrolled systemic lupus erythematosus
18. Uncontrolled pleural/pericardial effusions or ascites
19. New invasive cancer except non-melanoma skin cancers
20. Invasive fungal or viral infection
21. Inability to tolerate oral medications
22. Total bilirubin>2x upper limit of normal
23. Subjects taking medications that are sensitive to substrates or substrates with a narrow therapeutic range for CYP3A4, CYP2C8, CYP2C9, or CYP2D6 or strong inhibitors or inducers of CYP3A4 (e.g. cyclosporine, tacrolimus or sirolimus). If antifungals are absolutely necessary from an infectious disease perspective, then they will be allowed only if the levels are therapeutic.
24. Subjects on strong inhibitors of CYP3A4.
25. Subjects on therapeutic doses of anticoagulants (Warfarin (Coumadin);Rivaroxaban (Xarleto); Apixaban (Eliquis); Dabigatran (Pradaxa, Prazaxa) or Other).
26. Subjects on antiplatelet agents ((Clopidogrel (Plavix); Dipyridamole + Asprin (Aggrenox); Ticagrelor (Brilinta); Prasugrel (Effient); Ticlopidine (Ticlid) or Other) who are unable or unwilling to reduce or hold therapy prior to and during the 3-day drug dosing. Subjects may continue their previous regimen on day 4.
27. Subjects on quinolone antibiotic therapy for treatment or for prevention of infections within 10 days
28. Subjects taking H2-antagonists or proton pump inhibitors and unwilling to discontinue therapy 1 week prior and 2 weeks following enrollment.
29. Corrected QT interval (QTc)>450 msec
30. 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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
No Intervention: Group 1: Observational; Observational Only
Active Comparator: Group 2: Dasatinib & Quercetin; The drugs dasatinib and quercetin will be used in this arm	Drug: Group 2: Dasatinib; Dasatinib - take one 100 mg tablet by mouth once daily for 3 consecutive days.; Other Names: Sprycel; Drug: Group 2: Quercetin; Quercetin - take four 250 mg capsules daily (total 1000 mg daily) for 3 consecutive days.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in proportion of senescent cells (representing the total senescent cell burden) present	Assessment of senescence markers in skin, fat, and/or blood at baseline and day 14.	Baseline, Day 14

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in proportion of senescent mesenchymal stem cells present	Assessment of senescence markers in mesenchymal stem cells at baseline and day 14.	Baseline, Day 14
Change in mesenchymal stem cell function	Assessment of functional studies in mesenchymal stem cells at baseline and day 14. Number of subjects with change in stem cell function related to treatment.	Baseline, Day 14
Change in Frailty index score	Assessment by Fried and other frailty criteria at baseline and day 14.	Baseline, Day 14
Change in kidney function	Assessment by estimated and measured glomerular filtration rate at baseline, day 14, month 4, and month 12.	Baseline, Day 14, Month 4, Month 12

Collaborators and Investigators

• Sponsor: Mayo Clinic
• Investigators: Principal Investigator: LaTonya J Hickson, MD, Mayo Clinic

Publications and helpful links

General Publications

• Hickson LJ, Langhi Prata LGP, Bobart SA, Evans TK, Giorgadze N, Hashmi SK, Herrmann SM, Jensen MD, Jia Q, Jordan KL, Kellogg TA, Khosla S, Koerber DM, Lagnado AB, Lawson DK, LeBrasseur NK, Lerman LO, McDonald KM, McKenzie TJ, Passos JF, Pignolo RJ, Pirtskhalava T, Saadiq IM, Schaefer KK, Textor SC, Victorelli SG, Volkman TL, Xue A, Wentworth MA, Wissler Gerdes EO, Zhu Y, Tchkonia T, Kirkland JL. Senolytics decrease senescent cells in humans: Preliminary report from a clinical trial of Dasatinib plus Quercetin in individuals with diabetic kidney disease. EBioMedicine. 2019 Sep;47:446-456. doi: 10.1016/j.ebiom.2019.08.069. Epub 2019 Sep 18. Erratum In: EBioMedicine. 2020 Feb;52:102595.

Helpful Links

• Mayo Clinic Clinical Trials

Study record dates

Study Major Dates

• Study Start (Actual): July 1, 2016
• Primary Completion (Estimated): April 1, 2025
• Study Completion (Estimated): April 1, 2025

Study Registration Dates

• First Submitted: March 22, 2016
• First Submitted That Met QC Criteria: July 27, 2016
• First Posted (Estimated): July 28, 2016

Study Record Updates

• Last Update Posted (Actual): April 19, 2024
• Last Update Submitted That Met QC Criteria: April 18, 2024
• Last Verified: April 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Urologic Diseases; Disease Attributes; Renal Insufficiency; Chronic Disease; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Kidney Diseases; Renal Insufficiency, Chronic; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Protective Agents; Protein Kinase Inhibitors; Antioxidants; Tyrosine Kinase Inhibitors; Dasatinib; Quercetin
• Other Study ID Numbers: 15-005843

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No