RESTOR [Rapamycin and Everolimus Study Towards Older Rejuvenation]: An Exploratory PK/PD Study of mTOR Inhibition in Older Human Subjects
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 入组人数
- 194
- 试验地点
- 2
- 主要终点
- Level of Soluble Intercellular Adhesion Molecule-1 (sICAM-1)
研究概览
简要总结
As people get older, there are changes in their cells and tissues that may affect their ability to function. This can lead to increased death and age-associated disorders, like heart disease, cancer, and Alzheimer's disease. Studies in animal models have been able to identify drugs that slow the aging process, leading to a longer, healthier life. This study is focused on one such family of drugs, called mTOR inhibitors, and the investigators' goal is to test two of these drugs, Rapamycin (Sirolimus) and Everolimus (Afinitor), in healthy older adults to find a dose and dose timing that can be used to safely inhibit mTOR to the levels seen in young healthy persons. The investigators expect that the dose that works well in women may differ from the one that is best in men, so it is important to include both sexes in this research.
详细描述
The study will be done in three parts, each with different human subject groups. Participants may only enroll in one of the sub-studies.
Sub-study 1: Determining target mTOR activity values in YOUNG untreated subjects (ages 20-30 years): NOTE: This aim of the study is not a clinical trial, so this population will not be included in participant flow or included as an arm in the study.
This study defines "best dose" as the choice of drug, dose, and frequency that will come closest to restoring the "youthful" levels of mTOR activity in an older individual. The investigators first need to measure mTOR activity in young untreated subjects to define these target "youthful" mTOR activity levels.
Sub-study 2. Finding the most effective drug, dose, and timing for dosing for oral dosing of the mTOR inhibitor drugs in older adults (65-90 years):
Healthy older persons will be recruited for a short-term (6 week treatment plus 4 week follow-up) dose-finding study. The most effective, but safe dose will then be tested in a larger number of subjects in Sub-study 3. Importantly, the best drug and dose regimen for females may differ from the one determined for males so the cohort will include both sexes.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Sequential
- 主要目的
- Basic Science
- 盲法
- Double (Participant, Care Provider)
盲法说明
Blinding will only occur in Aim 2 (Sub-study 3). Randomization will be done by the research pharmacy providing the investigational drug.
入排标准
- 年龄范围
- 65 Years 至 90 Years（Older Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •Older Cohort Sub-study 2 (AIM 1) and Sub-study 3 (AIM 2):
- •Age ≥65 to 90 years
- •Men and women
- •In good health with all medical problems stable.
- •Community-dwelling
- •Agreement to adhere to Lifestyle Considerations throughout study duration.
- •Ability of participant to understand and the willingness to sign a written informed consent document.
排除标准
- •Older Cohort Sub-study 2 (AIM 1) and Sub-study 3 (AIM 2):
- •Resident of nursing home or long-term care facility
- •Subjects with diabetes or currently taking glucose lowering medications
- •History of moderate-severe heart disease (New York Heart Classification greater than grade II) or pulmonary disease (dyspnea on exertion upon climbing one flight of stairs or less; abnormal breath sounds on auscultation); Moderate to severe valvular heart disease
- •Active cancer or history of cancer treatment within the last 5 years
- •Chronic inflammatory condition, autoimmune disease, or infectious processes (e.g., active tuberculosis, HIV, rheumatoid arthritis, systemic lupus erythematosus, acute or chronic hepatitis B or C)
- •History of a coagulopathy or any medical condition requiring anticoagulation (except low dose ASA)
- •Renal insufficiency with an estimated glomerular filtration rate of <30ml/min
- •Uncontrolled hypercholesterolemia >350mg/dl or uncontrolled hypertriglyceridemia >500mg/dl
- •Anemia or abnormal blood cell counts: hemoglobin level <9.0g.dl; white blood count <3500/mm3; neutrophil count <2000/ mm3; platelet count <125,000/mm3
- •History of skin ulcers or poor wound healing
- •Active tobacco use (within 6 months)
- •Diagnosis of any disabling neurologic disease such as Parkinson's Disease, Amyotrophic Lateral Sclerosis, multiple sclerosis, cerebrovascular accident with residual deficits (muscle weakness or gait disorder), severe neuropathy, diagnosis of dementia or Clox1 score less than 10 at the time of screening visit, cognitive impairment due to any reason such that the patient is unable to provide informed consent
- •Liver disease
- •Systemic treatment with an immunosuppressant (prednisone, etc.) within the year prior to enrollment
- •Treatment with drugs known to affect cytochrome P450 (CYP3A4), i.e., diltiazem, erythromycin.
- •Patients with history of recent (within 6 months) myocardial infarction or active coronary disease
- •Patients with history of recent (within 6 months) intestinal disorders
- •History of severe head trauma, brain injury, brain surgery, inflammation of the brain, or history of seizure disorder
- •History of Long-Covid (PASC) within one year
- •Acute Covid19 or Covid19 infection within the last 6 months
- •Unwilling to forgo grapefruit juice consumption.
- •Participation in mTORi study within the prior year. (Note: participants in AIM 1 will be excluded from participating in AIM 2 of the proposed trial.)
- •Allergic to RAPA or EVERO
- •Allergic to lidocaine
- •Recreational drug use
- •Donated blood over a two-month period prior to study initiation.
- •Currently using cannabidiol (CBD) or tetrahydrocannabinol (THC) or any preparation contained these, or related, substances.
- •Currently using hormone replacement or modulating therapies.
研究组 & 干预措施
Aim 2: Sub-study 3 Placebo control
Daily administration of a placebo will be given to a cohort of older human subjects. Both males and females will be enrolled as controls.
干预措施: Placebo (Other)
Aim 2: Sub-study 3 Optimized INTERMITTENT Dosing of an mTOR inhibitor
Based on the findings from Aim 1, the optimal drug (RAPA or EVERO), interval between doses, and dose for INTERMITTENT delivery will be tested in a blinded placebo-controlled trial in older human subjects. The drug/dose/interval used in males may differ from the one used in females as the OD will be determined independently for the two sexes. PD parameters 'downstream' from mTOR will be followed. Although drug is delivered on an intermittent schedule, subjects will be given a pill each day (either drug or placebo, as scheduled) to maintain blinding.
干预措施: Everolimus (Drug)
Aim 1: Sub-study 2 Intermittent dosing Cohort Everolimus
Aim 1 is an open label, adaptive, dose finding PK/PD trial in older women and men.
In sub-study 2 (part of Aim 1), an older cohort will be studied to determine the optimal dose (OD) in milligrams and the optimal interval for intermittent delivery of everolimus (EVERO) based on changes in PD parameters 'downstream' from mTOR. Based on the data acquired, additional older cohorts will be tested at higher/lower doses in an adaptive, step-wise trial design.
干预措施: Everolimus (Drug)
Aim 1:Sub-study 2 Daily dosing Cohort Rapamycin
Aim 1 is an open label, adaptive, dose finding PK/PD trial in older women and men.
In sub-study 2 (part of Aim 1), an older cohort will be studied to determine the optimal dose (OD) in milligrams of rapamycin (RAPA) based on changes in PD parameters 'downstream' from mTOR. Based on the data acquired, additional older cohorts will be tested at higher/lower doses in an adaptive, step-wise trial design.
干预措施: Rapamycin (Drug)
Aim 2: Sub-study 3 Optimized DAILY Dose of an mTOR inhibitor
Based on the findings from Aim 1, the optimal drug (RAPA or EVERO) and dose for DAILY delivery will be tested in a blinded placebo-controlled trial in older human subjects. The drug/dose used in males may differ from the one used in females as the OD will be determined independently for the two sexes. PD parameters 'downstream' from mTOR will be followed.
干预措施: Everolimus (Drug)
Aim 2: Sub-study 3 Optimized INTERMITTENT Dosing of an mTOR inhibitor
Based on the findings from Aim 1, the optimal drug (RAPA or EVERO), interval between doses, and dose for INTERMITTENT delivery will be tested in a blinded placebo-controlled trial in older human subjects. The drug/dose/interval used in males may differ from the one used in females as the OD will be determined independently for the two sexes. PD parameters 'downstream' from mTOR will be followed. Although drug is delivered on an intermittent schedule, subjects will be given a pill each day (either drug or placebo, as scheduled) to maintain blinding.
干预措施: Rapamycin (Drug)
Aim 1: Sub-study 2 Daily dosing Cohort Everolimus
Aim 1 is an open label, adaptive, dose finding PK/PD trial in older women and men.
In sub-study 2 (part of Aim 1), an older cohort will be studied to determine the optimal dose (OD) of everolimus (EVERO) in milligrams based on changes in PD parameters 'downstream' from mTOR. Based on the data acquired, additional older cohorts will be tested at higher/lower doses in an adaptive, step-wise trial design.
干预措施: Everolimus (Drug)
Aim 1:Sub-study 2 Intermittent dosing Cohort Rapamycin
Aim 1 is an open label, adaptive, dose finding PK/PD trial in older women and men.
In sub-study 2 (part of Aim 1), an older cohort will be studied to determine the optimal dose (OD) in milligrams and the optimal interval for intermittent delivery of rapamycin (RAPA) based on changes in PD parameters 'downstream' from mTOR. Based on the data acquired, additional older cohorts will be tested at higher/lower doses in an adaptive, step-wise trial design.
干预措施: Rapamycin (Drug)
Aim 2: Sub-study 3 Optimized DAILY Dose of an mTOR inhibitor
Based on the findings from Aim 1, the optimal drug (RAPA or EVERO) and dose for DAILY delivery will be tested in a blinded placebo-controlled trial in older human subjects. The drug/dose used in males may differ from the one used in females as the OD will be determined independently for the two sexes. PD parameters 'downstream' from mTOR will be followed.
干预措施: Rapamycin (Drug)
结局指标
主要结局
Level of Soluble Intercellular Adhesion Molecule-1 (sICAM-1)
时间窗: Baseline to study end (approximately 12 months)
The level of soluble (s)ICAM-1 will be measured in serum.
Pharmacokinetics (PK) of mTOR inhibitor in blood
时间窗: Baseline to study end (approximately 12 months for Aim 2; 12 weeks for Aim 1)
The levels of the study drug will be measured in whole blood
PD measure of inhibition of mTOR activity in blood cells - p-rpS6
时间窗: Baseline to study end (approximately 12 months for Aim 2; 12 weeks for Aim 1)
Proteins prepared from PBMCs (peripheral blood mononuclear cells) will be analyzed for phosphorylation of ribosomal protein S6, downstream of mTORC1.
Level of Soluble Intercellular Adhesion Molecule-1 (sICAM-1)
时间窗: Baseline to study end (approximately 12 months)
The level of soluble (s)ICAM-1 will be measured in serum.
次要结局
- PD measure of inhibition of mTOR activity in muscle (Aim 2 only) - pS6K(Baseline to study end (approximately 12 months))
- PD measure of inhibition of mTOR activity in adipose cells, rpS6 (Aim 2 only)(Baseline to study end (approximately 12 months))
- PD measure of inhibition of mTOR activity in muscle rpS6 (Aim 2 only)(Baseline to study end (approximately 12 months))
- PD measure of inhibition of mTOR activity in adipose (fat) cells Akt (Aim 2 only)(Baseline to study end (approximately 12 months))
- PK of mTOR inhibitor in fat (Aim 2 only)(Baseline and study end (approximately 12 months))
- PK of mTOR inhibitor in muscle (Aim 2 only)(Baseline to study end (approximately 12 months))
- PD measure of inhibition of mTOR activity in fat cells (Aim 2 only) - pS6K(Baseline to study end (approximately 12 months))
- PD measure of inhibition of mTOR activity in muscle Akt (Aim 2 only)(Baseline to study end (approximately 12 months))
- PK of mTOR inhibitor in fat (Aim 2 only)(Baseline and study end (approximately 12 months))
- PK of mTOR inhibitor in muscle (Aim 2 only)(Baseline to study end (approximately 12 months))
- PD measure of inhibition of mTOR activity in muscle (Aim 2 only) - pS6K(Baseline to study end (approximately 12 months))
- PD measure of inhibition of mTOR activity in fat cells (Aim 2 only) - pS6K(Baseline to study end (approximately 12 months))
- PD measure of inhibition of mTOR activity in PBMCs, S6-kinase(Baseline to study end (approximately 12 months))
- PD measure of inhibition of mTOR activity in adipose cells, rpS6 (Aim 2 only)(Baseline to study end (approximately 12 months))
- PD measure of inhibition of mTOR activity in adipose (fat) cells Akt (Aim 2 only)(Baseline to study end (approximately 12 months))
- PD measure of inhibition of mTOR activity in muscle rpS6 (Aim 2 only)(Baseline to study end (approximately 12 months))
- PD measure of inhibition of mTOR activity in muscle Akt (Aim 2 only)(Baseline to study end (approximately 12 months))
- PD measure of inhibition of mTOR activity in PBMCs Akt(Baseline to study end (approximately 12 months))
研究者
Ellen Kraig
Professor
The University of Texas Health Science Center at San Antonio