Senescence in Chronic Kidney Disease

• ClinicalTrials.gov Identifier: NCT02848131
• Recruitment Status: Enrolling by invitation
• First Posted: July 28, 2016
• Last Update Posted: April 4, 2023
• Sponsor: Mayo Clinic
• Information provided by (Responsible Party): LaTonya J. Hickson, Mayo Clinic

Study Description

Brief Summary:

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).

Condition or disease	Intervention/treatment	Phase
Chronic Kidney Disease	Drug: Group 2: Dasatinib; Drug: Group 2: Quercetin	Phase 2

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 Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 30 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Senescence, Frailty, and Mesenchymal Stem Cell Functionality in Chronic Kidney Disease: Effect of Senolytic Agents
• Actual Study Start Date: July 2016
• Estimated Primary Completion Date: April 2025
• Estimated Study Completion Date: April 2025

Arms and Interventions

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 Name: Sprycel; Drug: Group 2: Quercetin; Quercetin - take four 250 mg capsules daily (total 1000 mg daily) for 3 consecutive days.

Outcome Measures

Primary Outcome Measures :

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

Secondary Outcome Measures :

1. Change in proportion of senescent mesenchymal stem cells present [ Time Frame: Baseline, Day 14 ]
   Assessment of senescence markers in mesenchymal stem cells at baseline and day 14.
2. Change in mesenchymal stem cell function [ Time Frame: Baseline, Day 14 ]
   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.
3. Change in Frailty index score [ Time Frame: Baseline, Day 14 ]
   Assessment by Fried and other frailty criteria at baseline and day 14.
4. Change in kidney function [ Time Frame: Baseline, Day 14, Month 4, Month 12 ]
   Assessment by estimated and measured glomerular filtration rate at baseline, day 14, month 4, and month 12.

Eligibility Criteria

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

Criteria

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.

Contacts and Locations

Locations

United States, Florida

Mayo Clinic Florida

Jacksonville, Florida, United States, 32224

United States, Minnesota

Mayo Clinic in Rochester

Rochester, Minnesota, United States, 55905

Sponsors and Collaborators

Mayo Clinic

Investigators

• Principal Investigator: LaTonya J Hickson, MD; Mayo Clinic

  Study Documents (Full-Text)

Documents provided by LaTonya J. Hickson, Mayo Clinic:

Study Protocol and Statistical Analysis Plan  [PDF] April 19, 2019

More Information

Additional Information:

Mayo Clinic Clinical Trials 

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

• Responsible Party: LaTonya J. Hickson, Principal Investigator, Mayo Clinic
• ClinicalTrials.gov Identifier: NCT02848131
• Other Study ID Numbers: 15-005843
• First Posted: July 28, 2016
• Last Update Posted: April 4, 2023
• Last Verified: April 2023

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:

Kidney Diseases; Renal Insufficiency, Chronic; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Renal Insufficiency; Chronic Disease; Disease Attributes; Pathologic Processes; Dasatinib; Quercetin; Antineoplastic Agents; Protein Kinase Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action; Antioxidants; Protective Agents; Physiological Effects of Drugs