Senescence in Chronic Kidney Disease
Primary Purpose
Chronic Kidney Disease
Status
Enrolling by invitation
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Group 2: Dasatinib
Group 2: Quercetin
Sponsored by
About this trial
This is an interventional treatment trial for Chronic Kidney Disease
Eligibility Criteria
Inclusion Criteria:
- Age 40-80 years
- Chronic kidney disease estimated glomerular filtration rate (eGFR) 15-45 ml/min/1.73m2
- Diabetes mellitus and taking diabetes medications
Exclusion Criteria:
- Concomitant glomerulonephritis,
- Nephrotic syndrome,
- Solid organ transplantation,
- Autosomal dominant or recessive polycystic kidney disease,
- Known renovascular disease,
- Pregnancy,
- Active immunosuppression therapy,
- Hemoglobin A1c≥10% at screening,
- History of active substance abuse (including alcohol) within the past 2 years,
- Current alcohol abuse (>3 alcoholic beverages/day or >21 per week),
- Body weight >150 kg or body mass index>50
- Human immunodeficiency virus infection
- Active hepatitis B or C infection
- Tyrosine kinase inhibitor therapy
- Known hypersensitivity or allergy to dasatinib or quercetin
- Inability to give informed consent
- 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
- Total bilirubin>2x upper limit of normal
- 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.
- Subjects on strong inhibitors of CYP3A4.
- Subjects on therapeutic doses of anticoagulants (Warfarin (Coumadin);Rivaroxaban (Xarleto); Apixaban (Eliquis); Dabigatran (Pradaxa, Prazaxa) or Other).
- 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.
- Subjects on quinolone antibiotic therapy for treatment or for prevention of infections within 10 days
- Subjects taking H2-antagonists or proton pump inhibitors and unwilling to discontinue therapy 1 week prior and 2 weeks following enrollment.
- Corrected QT interval (QTc)>450 msec
- 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.
Sites / Locations
- Mayo Clinic Florida
- Mayo Clinic in Rochester
Arms of the Study
Arm 1
Arm 2
Arm Type
No Intervention
Active Comparator
Arm Label
Group 1: Observational
Group 2: Dasatinib & Quercetin
Arm Description
Observational Only
The drugs dasatinib and quercetin will be used in this arm
Outcomes
Primary Outcome Measures
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.
Secondary Outcome Measures
Change in proportion of senescent mesenchymal stem cells present
Assessment of senescence markers in mesenchymal stem cells at baseline and 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.
Change in Frailty index score
Assessment by Fried and other frailty criteria at baseline and day 14.
Change in kidney function
Assessment by estimated and measured glomerular filtration rate at baseline, day 14, month 4, and month 12.
Full Information
1. Study Identification
Unique Protocol Identification Number
NCT02848131
Brief Title
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
2. Study Status
Record Verification Date
April 2023
Overall Recruitment Status
Enrolling by invitation
Study Start Date
July 2016 (Actual)
Primary Completion Date
April 2025 (Anticipated)
Study Completion Date
April 2025 (Anticipated)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Mayo Clinic
4. Oversight
Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No
5. 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).
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Chronic Kidney Disease
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
30 (Anticipated)
8. Arms, Groups, and Interventions
Arm Title
Group 1: Observational
Arm Type
No Intervention
Arm Description
Observational Only
Arm Title
Group 2: Dasatinib & Quercetin
Arm Type
Active Comparator
Arm Description
The drugs dasatinib and quercetin will be used in this arm
Intervention Type
Drug
Intervention Name(s)
Group 2: Dasatinib
Other Intervention Name(s)
Sprycel
Intervention Description
Dasatinib - take one 100 mg tablet by mouth once daily for 3 consecutive days.
Intervention Type
Drug
Intervention Name(s)
Group 2: Quercetin
Intervention Description
Quercetin - take four 250 mg capsules daily (total 1000 mg daily) for 3 consecutive days.
Primary Outcome Measure Information:
Title
Change in proportion of senescent cells (representing the total senescent cell burden) present
Description
Assessment of senescence markers in skin, fat, and/or blood at baseline and day 14.
Time Frame
Baseline, Day 14
Secondary Outcome Measure Information:
Title
Change in proportion of senescent mesenchymal stem cells present
Description
Assessment of senescence markers in mesenchymal stem cells at baseline and day 14.
Time Frame
Baseline, Day 14
Title
Change in mesenchymal stem cell function
Description
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.
Time Frame
Baseline, Day 14
Title
Change in Frailty index score
Description
Assessment by Fried and other frailty criteria at baseline and day 14.
Time Frame
Baseline, Day 14
Title
Change in kidney function
Description
Assessment by estimated and measured glomerular filtration rate at baseline, day 14, month 4, and month 12.
Time Frame
Baseline, Day 14, Month 4, Month 12
10. Eligibility
Sex
All
Minimum Age & Unit of Time
40 Years
Maximum Age & Unit of Time
80 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
Age 40-80 years
Chronic kidney disease estimated glomerular filtration rate (eGFR) 15-45 ml/min/1.73m2
Diabetes mellitus and taking diabetes medications
Exclusion Criteria:
Concomitant glomerulonephritis,
Nephrotic syndrome,
Solid organ transplantation,
Autosomal dominant or recessive polycystic kidney disease,
Known renovascular disease,
Pregnancy,
Active immunosuppression therapy,
Hemoglobin A1c≥10% at screening,
History of active substance abuse (including alcohol) within the past 2 years,
Current alcohol abuse (>3 alcoholic beverages/day or >21 per week),
Body weight >150 kg or body mass index>50
Human immunodeficiency virus infection
Active hepatitis B or C infection
Tyrosine kinase inhibitor therapy
Known hypersensitivity or allergy to dasatinib or quercetin
Inability to give informed consent
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
Total bilirubin>2x upper limit of normal
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.
Subjects on strong inhibitors of CYP3A4.
Subjects on therapeutic doses of anticoagulants (Warfarin (Coumadin);Rivaroxaban (Xarleto); Apixaban (Eliquis); Dabigatran (Pradaxa, Prazaxa) or Other).
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.
Subjects on quinolone antibiotic therapy for treatment or for prevention of infections within 10 days
Subjects taking H2-antagonists or proton pump inhibitors and unwilling to discontinue therapy 1 week prior and 2 weeks following enrollment.
Corrected QT interval (QTc)>450 msec
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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
LaTonya J Hickson, MD
Organizational Affiliation
Mayo Clinic
Official's Role
Principal Investigator
Facility Information:
Facility Name
Mayo Clinic Florida
City
Jacksonville
State/Province
Florida
ZIP/Postal Code
32224
Country
United States
Facility Name
Mayo Clinic in Rochester
City
Rochester
State/Province
Minnesota
ZIP/Postal Code
55905
Country
United States
12. IPD Sharing Statement
Plan to Share IPD
No
Citations:
PubMed Identifier
31542391
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. Erratum In: EBioMedicine. 2020 Feb;52:102595.
Results Reference
derived
Links:
URL
https://www.mayo.edu/research/clinical-trials
Description
Mayo Clinic Clinical Trials
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Senescence in Chronic Kidney Disease
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