Clinical trial NCT02848131: Senescence in Chronic Kidney Disease
Official title: Senescence, Frailty, and Mesenchymal Stem Cell Functionality in Chronic Kidney Disease: Effect of Senolytic Agents
Study type: INTERVENTIONAL
Overall status: ENROLLING_BY_INVITATION
Phase: PHASE2
Conditions: Chronic Kidney Disease
Lead sponsor: Mayo Clinic
Sponsor class: OTHER
First posted: 2016-07-28
Enrollment: 30
Sex: ALL
Minimum age (years): 40
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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).

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.

Eligibility 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.

Primary outcomes:
measure: Change in proportion of senescent cells (representing the total senescent cell burden) present
timeFrame: Baseline, Day 14
Secondary outcomes:
measure: Change in proportion of senescent mesenchymal stem cells present
timeFrame: Baseline, Day 14
measure: Change in mesenchymal stem cell function
timeFrame: Baseline, Day 14
measure: Change in Frailty index score
timeFrame: Baseline, Day 14
measure: Change in kidney function
timeFrame: Baseline, Day 14, Month 4, Month 12
Other outcomes:
Locations:
city: Jacksonville
country: United States
facility: Mayo Clinic Florida
state: Florida
city: Rochester
country: United States
facility: Mayo Clinic in Rochester
state: Minnesota
Study officials:
affiliation: Mayo Clinic
name: LaTonya J Hickson, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.