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Impacts of Mechanistic Target of Rapamycin (mTOR) Inhibition on Aged Human Muscle (Rapamune) (Rapamune)

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ClinicalTrials.gov Identifier: NCT05414292
Recruitment Status : Recruiting
First Posted : June 10, 2022
Last Update Posted : June 10, 2022
Sponsor:
Collaborator:
University of Oxford
Information provided by (Responsible Party):
Philip Atherton, University of Nottingham

Brief Summary:

As people age, muscle mass and function is lost and exercise training is an important way to reduce the effects of this and remain independent. However, not everyone can perform this exercise and the muscle responses to exercise are often reduced in older people. So far there has been no drug found to specifically treat or reduce this problem.

Muscle size depends on the balance of muscle protein breakdown and synthesis (building). This balance is regulated by multiple signals within the body, but a particular molecule - the mechanistic target of rapamycin (mTOR), is known to play an important role. For protein synthesis to build up the muscles, this pathway is needed to start the process when triggered by eating protein or exercise. Although this would suggest that mTOR activity is good, excessive levels of this signalling seem to have negative impacts on muscle maintenance with age.

In animal studies, blocking mTOR signalling has stopped the development of a number of age-related diseases and increased health-span. Drugs that block this pathway (e.g. Rapamune) reduce the stimulation of muscle protein synthesis, possibly through changing the immune system, but conversely have also been shown to increase muscle size and reduce markers of nerve supply loss. This means that drugs which block the mTOR pathway could, in older people, help to reduce the negative impacts of excessive mTOR signalling on muscle size and function.

The investigators aim to recruit 16 healthy male volunteers over 50 years old to investigate how the drug Rapamune (which blocks the mTOR pathway) affects aged human muscle both on its own and when combined with resistance exercise training.


Condition or disease Intervention/treatment Phase
Muscle Atrophy Age-Related Sarcopenia Drug: Rapamune (sirolimus) 1Mg Tablet Behavioral: Unilateral resistance exercise training Not Applicable

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 16 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single (Participant)
Masking Description: Participant will not know if they are taking Rapamune or placebo
Primary Purpose: Health Services Research
Official Title: Impacts of Mechanistic Target of Rapamycin (mTOR) Inhibition on Aged Human Muscle.
Actual Study Start Date : August 6, 2021
Estimated Primary Completion Date : May 1, 2024
Estimated Study Completion Date : May 1, 2024

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Drug group
Will take 1mg Rapamune (sirolimus) in oral tablet form daily for 16 weeks.
Drug: Rapamune (sirolimus) 1Mg Tablet
Take Rapamune to see the effect on muscle structure and function during a 14 week unilateral resistance exercise training programme.
Other Names:
  • Rapamycin
  • Sirolimus
  • Rapamune

Behavioral: Unilateral resistance exercise training
Participants will complete unilateral leg extension resistance training 3 times per week for 14 weeks at 75% of their 1 repetition maximum
Other Names:
  • Leg extension
  • Strength training

Placebo Comparator: Placebo group
Will take a placebo tablet (lactose) daily for 16 weeks
Behavioral: Unilateral resistance exercise training
Participants will complete unilateral leg extension resistance training 3 times per week for 14 weeks at 75% of their 1 repetition maximum
Other Names:
  • Leg extension
  • Strength training




Primary Outcome Measures :
  1. Change in muscle mass from baseline [ Time Frame: 0 and 16 weeks ]
    To determine the impacts of rapamycin, an mTOR inhibitor, on human muscle mass through whole body muscle mass measures by MRI and D3 creatine tracer, and ultrasound of the thigh muscles.

  2. Change in muscle mass from baseline [ Time Frame: 0 and 8 weeks ]
    To determine the impacts of rapamycin, an mTOR inhibitor, on human muscle mass through whole body muscle mass measures by MRI and D3 creatine tracer, and ultrasound of the thigh muscles.

  3. Change in muscle mass from baseline [ Time Frame: 0 and 5 weeks ]
    To determine the impacts of rapamycin, an mTOR inhibitor, on human muscle mass through whole body muscle mass measures by MRI and D3 creatine tracer, and ultrasound of the thigh muscles.


Secondary Outcome Measures :
  1. Change in muscle strength [ Time Frame: 0, 5, 8 and 16 weeks ]
    To determine the impacts of rapamycin on muscle function through muscle strength measures of 1 Repetition Maximum

  2. Change in muscle power [ Time Frame: 0, 5, 8 and 16 weeks ]
    To determine the impacts of rapamycin on muscle function through muscle power measured from countermovement jump analysis.

  3. Change in muscle function [ Time Frame: 0, 5, 8 and 16 weeks ]
    To determine the impacts of rapamycin on muscle function through muscle performance measures included in the short performance physical battery test (SPPBT).

  4. Change in neuromuscular function [ Time Frame: 0, 5, 8 and 16 weeks ]
    • To determine the impacts of rapamycin on muscle function through muscle-nerve electrical signals studied with electromyography (EMG).

  5. Change in Muscle Protein Synthesis [ Time Frame: 2, 5, and 8 weeks ]
    To determine the impacts of rapamycin on muscle metabolism through effects on muscle protein synthesis (via D2O tracer) from muscle biopsies.

  6. Change in Muscle Protein Breakdown [ Time Frame: 2 and 16 weeks ]
    To determine the impacts of rapamycin on muscle metabolism through effects on muscle protein breakdown (via 3-MH tracer) obtained from muscle biopsies.



Information from the National Library of Medicine

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Ages Eligible for Study:   50 Years to 90 Years   (Adult, Older Adult)
Sexes Eligible for Study:   Male
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • Participant is willing and able to give informed consent for participation in the study
  • Participant is physically able to complete the resistance exercise training programme

Exclusion Criteria:

  • • A BMI <18 or >35 kg/m2

    • Active cardiovascular, cerebrovascular or respiratory disease: e.g. uncontrolled hypertension (BP > 160/100), angina, heart failure (class III/IV), arrhythmia, right to left cardiac shunt, recent cardiac event, COPD, pulmonary hypertension or recent stroke
    • Any metabolic disease
    • Clotting dysfunction
    • A history of, or current neurological or musculoskeletal conditions (e.g. epilepsy)
    • Having taken part in a research study in the last 3 months involving invasive procedures or an inconvenience allowance (this must remain for ALL UoN FMHS UREC approved studies)
    • Contraindications to MRI scanning including claustrophobia, pacemaker, metal implants etc. which will be assessed through an MRI safety screening questionnaire.
    • Contraindications to the use of Rapamycin e.g. those due scheduled vaccinations (as rapamycin can reduce the efficacy of vaccines).

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT05414292


Contacts
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Contact: Philip Atherton, PhD 01332724725 philip.atherton@nottingham.ac.uk

Locations
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United Kingdom
University of Nottingham School of Medicine Recruiting
Derby, United Kingdom, DE22 3DT
Contact: Philip Atherton         
Principal Investigator: Philip Atherton, PhD         
Sponsors and Collaborators
University of Nottingham
University of Oxford
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Responsible Party: Philip Atherton, Professor, University of Nottingham
ClinicalTrials.gov Identifier: NCT05414292    
Other Study ID Numbers: Rapamune_COMAP
First Posted: June 10, 2022    Key Record Dates
Last Update Posted: June 10, 2022
Last Verified: June 2022
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: Anonymised data may be shared with collaborators including anthropometric data and samples where consent is given for this.
Supporting Materials: Study Protocol
Analytic Code
Time Frame: The data will be available on conclusion of the study.
Access Criteria: Listed collaborators will have access on request with data given on approval by the principal investigator

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Sarcopenia
Muscular Atrophy
Atrophy
Pathological Conditions, Anatomical
Neuromuscular Manifestations
Neurologic Manifestations
Nervous System Diseases
Sirolimus
Anti-Bacterial Agents
Anti-Infective Agents
Antibiotics, Antineoplastic
Antineoplastic Agents
Antifungal Agents
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs