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Clinical Trial Details — Status: Recruiting

Administrative data

NCT number NCT05653258
Other study ID # STUDY00002506
Secondary ID R01AG075684
Status Recruiting
Phase Phase 2/Phase 3
First received
Last updated
Start date October 17, 2023
Est. completion date February 2027

Study information

Verified date January 2024
Source Cedars-Sinai Medical Center
Contact Nicolas Musi, MD
Phone 210-562-6140
Email nicolas.musi@cshs.org
Is FDA regulated No
Health authority
Study type Interventional

Clinical Trial Summary

All participants will undergo baseline biopsies of subcutaneous abdominal adipose tissue for cellular/molecular profiling via snRNA-seq and metabolic/physiological assessments (insulin sensitivity, glucose tolerance, and β-cell function). Older obese participants will be randomized into three arms: lifestyle intervention (n=24), senolytics (n=24), or placebo (n=24).


Description:

All participants after consent and enrollment will undergo adipose tissue single nuclei RNA sequencing and metabolic phenotyping. Subjects will undergo glucose tolerance testing to document glucose tolerance status. Each subject will be provided an accelerometer to be worn on their dominant wrist for 7 days for assessment of habitual activity. A dietitian will teach them to utilize the SmartIntake3 smartphone food picture application (app) for a 7-day food record. The app will be used to record amount of each meal consumed in order to determine daily food and beverage and supplement intake and quantity for dietary composition analysis. DEXA analysis will be performed to measure lean and fat body mass. Subjects will undergo evaluation of physical function/performance, including the Short Physical Performance Battery (SPPB) and VO2 peak testing for assessment of aerobic capacity. The SPPB will be done in older adults only. The NIH Patient-Reported Outcomes Measurement System (PROMIS) will be used to measure participants' self-report of symptoms, function, and health-related quality of life in the domains of physical, mental and social health. All subjects will undergo a two-step euglycemic insulin clamp and indirect calorimetry. Only older obese participants will continue to the randomization to likestyle intervention, senolytic agents or placebo.


Recruitment information / eligibility

Status Recruiting
Enrollment 160
Est. completion date February 2027
Est. primary completion date February 2026
Accepts healthy volunteers Accepts Healthy Volunteers
Gender All
Age group 18 Years and older
Eligibility Inclusion Criteria: 1. Both Sexes 2. Age: younger lean group 18-30 years with BMI 18.5-24.9 kg/m2; older lean group = 65 years with BMI 3. All races and ethnic groups 4. Community dwelling 5. Sedentary (=1.5 h of exercise per week) 6. Nondiabetic (fasting plasma glucose < 126 mg/dl, 2-h glucose during oral glucose tolerance test (OGTT) < 140mg/dl, and A1c < 6.5% 7. For all female participants who are women of childbearing potential (WOCBP), who are not pregnant or breast feeding, at least one of the following conditions must apply: A documented hysterectomy, bilateral salpingectomy, or bilateral oophorectomy Use of a contraceptive method that is highly effective (with a failure rate of <1% per year), preferably with low user dependency (implantable progesterone-only hormone contraception, intrauterine hormone releasing system, bilateral tubal occlusion, vasectomized partner) during the intervention period of the study and for at least 30 days after the last dose of study intervention to eliminate any reproductive safety risk of the study drug. Use of a contraceptive method that is highly effective (with a failure rate of <1% per year), with high user dependency, (oral/intravaginal/injectable combined estrogen and progesterone contraception, oral/injectable progesterone only hormone contraception, sexual abstinence) during the intervention period and for at least 30 days after the last dose of study intervention to eliminate any reproductive safety risk of the study drug. In addition to the highly effective methods: male or female condom with or without spermicide; cervical cap, diaphragm, or sponge with spermicide; a combination of male condom with either cervical cap, diaphragm, or sponge with spermicide. 8. ECG value after 10 minutes of resting in the supine position in the following ranges: 120ms<PR<220ms: QRS<120ms; QTc<430ms for males and QTc<450ms for females and normal ECG tracing, unless the investigator considers the ECG abnormality to be not clinically relevant. Exclusion Criteria: 1. Diabetes, clinically diagnosed or HbA1c > 6.5% and/or fasting plasma glucose > 126 mg/dl and/or use of anti-diabetic medications. 2. Participating in > 1.5 h of structured exercise/week 3. Unstable weight (>3% change in last 3 months) 4. Neurological, musculoskeletal, or other conditions that may limit subject's ability to complete study physical assessment and training 5. Active autoimmune/inflammatory disease including: rheumatoid arthritis, multiple sclerosis, systemic lupus erythematous, inflammatory bowel disease 6. Laboratory parameters outside the normal range: - impaired kidney function (eGFR < 30ml/min/1.73m² as calculated by the CKD-EPI equation); - impaired liver function (AST or ALT level > 2 times upper limit of normal (ULN); - total Bilirubin level > 1.5 times ULN; - TSH > 1.5 times ULN or < lower limit of normal (LLN); - Hemoglobin <10.0 g/dl; Platelets <125,000 cell/mm³; - Platelets < 125,000 cell/mm³ - Prothrombin time (PT) > 1.0 times ULN - Partial prothrombin time (PTT) > 1.0 times ULN. 7. Active gastrointestinal disease; coagulopathy; GI bleed within 6 months 8. Clinically significant heart disease (e.g. NYH Classification >II; ischemia) 9. Peripheral vascular disease (claudication) 10. QTc prolongation >45 msec 11. Use of anti-arrhythmic medications known to cause QTc prolongation, anti-platelet or anti-coagulant medication (see section 5.3) 12. Use of quinolone antibiotics or any other drugs that may prolong the QTc interval (see section 5.3) 13. Pulmonary disease (COPD), severe asthma or exercise-induced asthma 14. Recent systemic or pulmonary embolus 15. Uncontrolled blood pressure (systolic BP>170, diastolic BP>95 mmHg) 16. Smoking, alcohol use (history of regular alcohol consumption exceeding 7 drinks/week for female participants or 14 drinks/week for male participants. 1 drink = 5 ounces [150ml] of wine or 12 ounces [360ml] of beer or 1.5 ounces [45ml] of hard liquor) or recreational drug use 17. Pregnant or breastfeeding 18. Postmenopausal women new (within 6 months) to systemic hormone replacement therapy 19. Previous bariatric surgery 20. History of stroke with motor disability 21. Recent (3 years) treated cancer other than basal cell carcinoma 22. Acute or chronic infection 23. Medication that might interfere with metabolic studies (weight loss medication, systemic steroids, immunosuppressants) within 6 months (see section 5.3) 24. Potentially senolytic agents within the last 6 months: fisetin, quercetin, luteolin, dasatinib, piperlongumine, or navitoclax (see section 5.3) 25. History of allergy to dasatinib, quercetin and/or lidocaine.

Study Design


Related Conditions & MeSH terms


Intervention

Other:
Lifestyle Intervention
Exercise: Subjects will undergo a combined aerobic and resistance exercise intervention. The investigators propose a multi-modal training program because they improve metabolic outcomes and adding resistance training reduces the risk of muscle loss during weight loss. Subjects will exercise in the gym for three sessions per week for 10 weeks under supervision of an exercise physiologist. On each session, aerobic exercise will be followed by resistance exercise. Diet: The aim of the dietary intervention is to reduce caloric intake sufficient to result in 8-10% weight loss, while incorporating behavioral and dietary strategies to maximize adherence and to minimize risk of muscle and bone loss. Subjects will attend small-group sessions led by a dietitian for changing their dietary composition to follow American Heart Association (AHA)/American College of Cardiology (ACC) guidelines.
Drug:
Dasatinib 100 MG
100 mg of dasatinib (D) daily for 3 consecutive days plus quercetin (Q) for the same 3 consecutive days, followed by a 25-day (+/- 2 day) no-drug period to complete a single round. This will be repeated twice more until completing 3 rounds total in approximately 10 consecutive weeks.
Quercetin 1000mg
Quercetin (Q) (4) 250 mg capsules daily (total 1000 mg daily) plus dasatinib (D) same 3 consecutive days, followed by a 25-day (+/- 2 day) no-drug period to complete a single round. This will be repeated twice more until completing 3 rounds total in approximately 10 consecutive weeks.
Placebo
Subjects will receive a placebo (methylcellulose) to provide a similar mass, number of tablets/ capsules, and frequency as the senolytic arm.
Procedure:
Abdominal adipose tissue biopsy
All participants will undergo baseline biopsies of subcutaneous abdominal adipose tissue for cellular/molecular profiling via snRNA-seq

Locations

Country Name City State
United States Cedars Sinai Medical Center Los Angeles California

Sponsors (2)

Lead Sponsor Collaborator
Cedars-Sinai Medical Center National Institute on Aging (NIA)

Country where clinical trial is conducted

United States, 

Outcome

Type Measure Description Time frame Safety issue
Primary Insulin sensitivity Change in skeletal muscle insulin sensitivity Week 4 and Week 15
Primary Glucose tolerance Measurement of change in glucose tolerance using a glucose tolerance test Baseline to Week 14
Secondary Senescence-associated secretory phenotype (SASP) Measurement of change of SASP in adipose tissue Baseline to Week 16
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