Overview of clinical trial planned:
A 13-week, randomised, double-blind, placebo-controlled, Phase 2a Proof of concept trial of 30 participants, with 20 in the placebo arm and 10 in the Sirolimus (Rapamycin) arm. The patients shall complete a thrice-weekly group exercise program. The medications shall be taken once a week, and during the trial the exercise program shall be standardised.
Dosing: Sirolimus (Rapamycin) 5mg weekly dosing, or a placebo
Study Objectives
Primary Objective:
Assess the safety, tolerability, feasibility, and trial design of weekly Sirolimus (Rapamycin) 5mg or placebo dosing over a three-month period, in combination with thrice-weekly group exercise programs.
Secondary objective:
Assess the improvement in the 30-second chair-stand test after a three-month exercise training program. This will enable an appropriate power calculation to be conducted to inform the number of participants required for a superiority clinical trial.
Endpoints
Primary endpoint: 30-second (30-s) Chair Stand Test
Secondary endpoints:
- Muscle strength
- 1 repetition max of chest press and leg press
- Handgrip strength
- Muscle Endurance
- 6-minute walk test
- Community Balance & Mobility (CBM)
- Accelerometry
- Lean muscle mass as measured by DEXA scan
- Homeostatic Model Assessment for Insulin Resistance
- Full Blood Count, U&Es, LFTs, HbA1c, lipids, serum IGF-1 to ensure safety
- DNA methylation clocks
- Measure mTOR and senescence (expand on what markers)
Muscle Performance
To measure the effect exercise and weekly rapamycin dosing will have on the muscle performance of older adults, we have selected the 30-second chair-stand test as our primary outcome.
When measuring muscle performance, it is important to first define muscle strength, muscle power and muscle endurance. Muscle strength refers to “the amount of force a muscle can produce with a single maximal effort”. Muscle strength should be differentiated to muscle power which is defined by “the ability to exert a maximal force in as short a time as possible, as in accelerating, jumping and throwing implements” and to muscle endurance which is defined as “the ability of muscles to exert force against resistance over a sustained period of time” [32].
Compared to muscle strength, power concerns work rate (work done per unit time). In healthy older people, muscle power declines earlier and faster compared to muscle mass and strength. Leg power has been shown to be highly correlated with physical performance tests such as gait speed, chair stand test and stair-climb time, and several comparative studies have found that muscle power is a better predictor of mortality compared to muscle strength. Muscle power can be assessed across a range of muscle groups, but most often the leg press and knee extension exercises are used to measure muscle power. The 30-second (30-s) Chair stand test (CST) developed by Rikli and Jones is one of the most important physical performance clinical tests because it measures lower body power, balance and endurance and relates it to the most demanding daily life activities. The 30-s CST has been widely used in many studies not only to evaluate functional fitness levels but also to monitor training and rehabilitation[32].
It is also important to measure balance, but unfortunately the most commonly used balance tests suffer from ceiling effects in young seniors. A 2019 systematic review of performance-based clinical tests of balance and muscle strength used in young seniors concluded: “Based on the findings in this review, there seems to be only one promising scale for adequately assessing balance in healthy young seniors, i.e. showing no ceiling effects and having measures of high validity and reliability, namely the Community Balance & Mobility (CBM) scale” [33].
Brief Hypothesis
Periods of time where the mechanistic target of rapamycin (mTOR) pathway is activated via exercise, combined with alternate periods of time where mTOR is inhibited using Rapamycin, will result in greater muscle performance in older adults compared with just exercise alone.
In-depth Rationale and Hypothesis
Given its capability of blocking mTORC1 signalling, Rapamycin could be used to restore the mTORC1 balance and thereby improve exercise performance in older adults. mTORC1 is activated by branch-chain amino acids such as leucine or in response to an anabolic stimulus via exercise. However, overactivation of mTORC1 has been observed in aged human muscles, but this overactivation of mTORC1 in aged muscles does not induce protein synthesis. Instead, chronic mTORC1 activation in old muscle leads to muscle atrophy mainly due to the inability to induce autophagy, suggesting the importance of mTOR-induced regulation of autophagy in aged muscle [30]. Therefore, intermittent dosing with Rapamycin may restore the mTORC1 balance, whereby there are periods of mTORC1 activation and therefore protein synthesis, but also periods of mTORC1 inhibition with Rapamycin leading to autophagy. Plausibly, this approach may lead to an improvement in muscle performance of older adults. Furthermore, with a low and intermittent dosing regime, we aim to inhibit primarily mTORC1, thereby reducing the potential of adverse events.
The current FDA-approved use of the drug for, among others, the use as an immunosuppressant in organ transplants and the treatment of cancer is at doses that cause high levels of adverse events. The FDA-approved doses used for organ transplantation are much higher than the doses proposed for this study (5mg total, once a week):
- FDA-approved dose for kidney transplant rejection prophylaxis:
- Low dose: 3 mg/m2 per day, ↑ up to 40 mg/day max
- Medium dose: 6 mg/m2 per day, ↑ up to 40 mg/day max
- High dose: 15 mg per day, ↑ up to 40 mg/day max
Background
Aging & Muscle Strength
Human skeletal muscle inevitably undergoes remarkable changes with aging, characterized by a decline in muscle mass and strength of about 1% per year from the age of around 40 years[1]. A growing body of evidence suggests that muscular strength is inversely and independently associated with all-cause and cardiovascular mortality even after adjusting for cardiorespiratory fitness.[1] Ultimately, muscle wasting contributes significantly to weakness, disability, increased hospitalization, immobility, and loss of independence. Interventions for sarcopenia (the loss of skeletal muscle mass and strength as a result of aging) include exercise and nutrition because both have a positive impact on protein anabolism but also enhance other aspects that contribute to well-being in sarcopenic older adults, such as physical function, quality of life, and anti-inflammatory state.[1]
Selection of orally bioavailable Rapamycin Analogue
Pure Rapamycin has poor bioavailability, which lead to the development of the rapalogs: Sirolimus and Everolimus. Everolimus is a second generation Sirolimus derivative specifically developed to have improved pharmacokinetic properties including, but not limited to, facilitated oral formulation, higher oral bioavailability and better metabolic stability in comparison to sirolimus. As these regions of the Sirolimus and Everolimus molecules are structurally similar, it was hypothesized that both molecules have the same effects on the mTOR pathway, however this is not the case. Like Sirolimus, Everolimus inhibits mTORC1, but at the clinically relevant concentrations tested, Everolimus was much more effective at inhibiting mTORC2 [27].
It is important to note that the lifespan-enhancing effects of mTOR inhibitors have been linked to mTORC1 inhibition, whereas inhibition mTORC2 might even be detrimental, because mTORC2 controls insulin-mediated suppression of hepatic gluconeogenesis [28]. Therefore for this proposed trial, Sirolimus is the preferred rapamycin analogue as it does not inhibit mTORC2 to the same extent as Everolimus.
Inclusion/Exclusion Criteria
Inclusion
- Males and females aged ≥60 years and ≤70 years at the time of signing informed consent
- Medically stable and do not already perform regular strenuous exercise
- Capable of providing written informed consent and willing and able to adhere to all protocol requirements
- Participants must be reliable, compliant, and agree to cooperate with all planned future trial evaluations as explained in detail during the informed consent process and to be able to perform them.
Exclusion
- Already participating in strenuous activity enough to cause a noticeable increase in breathing more than twice a week
- Anaemia - Hg < 9.0 g/dl, Leukopenia - white blood cells (WBC) < 3,500/mm3 , Neutropenia - absolute neutrophil count < 2,000/mm3 , or Platelet count - platelet count < 125,000/mm3
- Older adults scheduled to undergo major surgery in the next
- Any uncontrolled or serious disease, or any medical (e.g. known active infection or major haematological, renal, metabolic, gastrointestinal, or endocrine dysfunction) or surgical that, in the opinion of the investigator , may interfere with participation in the clinical study and/or put the participant at significant risk.
- Malignancy (except non-melanoma skin cancers, cervical carcinoma in-situ) within the last 5 years.
- Known hypersensitivity, allergy, or any contraindication to Rapamycin or its excipients
- Fibromyalgia or Chronic Fatigue Syndrome/Myalgic Encephalomyelitis, Breast Implant Illness,
- Congestive heart failure: self-assessed functional status of heart failure New York Heart Association (NYHA) classification III or IV
- COPD Global Initiative for Chronic Obstructive Lung Disease (GOLD) classification III or IV
- Impaired renal function, as defined as glomerular filtration rate eGFR < 30
- Type 1 Diabetes
- Substance, alcohol or drug abuse within the 3 months prior to informed consent that would interfere with trial participation leading to decreased compliance with trial procedures or study medication intake in the opinion of the investigator
- Psychological, familial, sociological, or geographic factors potentially hampering compliance with the protocol, visits, or trial procedures or any other clinical condition that would jeopardise participant safety while participating in the clinical trial in the opinion of the investigator
- Those who have taken metformin, rapamycin, or rapalogs in the past 6 months
Full Clinical Trial details here: Clinical Trial Protocol - The Effect Of Regular Exercise & Intermittent Rapamycin Dosing On Muscle Performance In Older Adults
