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Trial registered on ANZCTR


Registration number
ACTRN12622000480785p
Ethics application status
Not yet submitted
Date submitted
5/03/2022
Date registered
25/03/2022
Date last updated
26/05/2023
Date data sharing statement initially provided
25/03/2022
Type of registration
Prospectively registered

Titles & IDs
Public title
The Effect of Regular Exercise & Intermittent Rapamycin Dosing On Muscle Performance In Older Adults
Scientific title
The Effect of Regular Exercise & Intermittent Rapamycin Dosing On Muscle Performance In Older Adults
Secondary ID [1] 306604 0
Nil known
Universal Trial Number (UTN)
U1111-1279-0901
Trial acronym
RAISE
Linked study record

Health condition
Health condition(s) or problem(s) studied:
sarcopenia 325513 0
Condition category
Condition code
Musculoskeletal 322889 322889 0 0
Other muscular and skeletal disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
This study is a test of an FDA-approved drug, Sirolimus (Rapamycin), being repurposed for the treatment of muscle aging in combination with exercise. The first phase is a proof-of-concept trial, designed to assess the safety, tolerability, feasibility, and trial design of weekly Sirolimus (Rapamycin) 6mg oral tablets or placebo dosing over a 13-week period, in combination with thrice-weekly at-home exercise programs. The trial will also assess improvement in the 30-Second Chair-Stand test after a 13-week exercise training program. This will enable an appropriate power calculation to be conducted to inform the number of patients required for a subsequent, superiority clinical trial.

Participants can be within 65-85 years of age at the time of enrolment, with either no co-morbidities or a well-controlled chronic condition, who do not already perform weekly, strenuous exercise. Participants will provide informed consent and undergo initial screening. If eligible, patients will be randomised in a 1:1 ratio to either the once-weekly placebo or Rapamycin group. In parallel to the oral medication, patients will engage three times a week in an at-home exercycle fitness program. The exercycles will be hired and delivered to the participants’ homes. Fitness-dependent exercise standardisation is important to minimise variance, particularly given that the primary outcome is a measure of exercise performance and can therefore be greatly influenced by the level of exercise training. To that end, here is the proposed exercycle training program:
Week 1: warm-up of 2 mins @ 50RPM, then 3 mins workout @70-80RPM @ very low resistance, then a cooldown of 2 mins @ 45RPM
Week 2: warm-up of 2 mins @ 50RPM, then 4 mins workout @70-80RPM @ very low resistance, then a cooldown of 2 mins @ 45RPM
Week 3: warm-up of 2 mins @ 50RPM, then 5 mins workout @70-80RPM @ very low resistance, then a cooldown of 2 mins @ 45RPM
Week 4: warm-up of 2 mins @ 50RPM, then 6 mins workout @70-80RPM @ very low resistance, then a cooldown of 2 mins @ 45RPM
Week 5: warm-up of 2 mins @ 50RPM, then 7 mins workout @70-80RPM @ low resistance, then a cooldown of 2 mins @ 45RPM
Week 6: warm-up of 2 mins @ 50RPM, then 8 mins workout @70-80RPM @ low resistance, then a cooldown of 2 mins @ 45RPM
Week 7: warm-up of 2 mins @ 50RPM, then 9 mins workout @70-80RPM @ low resistance, then a cooldown of 2 mins @ 45RPM
Week 8: warm-up of 2 mins @ 50RPM, then 10 mins workout @70-80RPM @ low resistance, then a cooldown of 2 mins @ 45RPM
Week 9: warm-up of 2 mins @ 50RPM, then 11 mins workout @70-80RPM @ medium resistance, then a cooldown of 2 mins @ 45RPM
Week 10: warm-up of 2 mins @ 50RPM, then 12 mins workout @70-80RPM @ medium resistance, then a cooldown of 2 mins @ 45RPM
Week 11: warm-up of 2 mins @ 50RPM, then 13 mins workout @70-80RPM @ medium resistance, then a cooldown of 2 mins @ 45RPM
Week 12: warm-up of 2 mins @ 50RPM, then 14 mins workout @70-80RPM @ medium resistance, then a cooldown of 2 mins @ 45RPM
Week 13: warm-up of 2 mins @ 50RPM, then 15 mins workout @70-80RPM @ medium resistance, then a cooldown of 2 mins @ 45RPM

All warm-ups and cooldown phases should be completed with a very low resistance setting.
If participants are unable to complete the exercycle training program due to difficulty, the program can be adjusted whereby the resistance setting is lowered. If a participant still cannot complete the training program, then they should aim to ride for as long as they can before moving to the cooldown phase.
In order to match the real-world setting, the exercycle program will not be supervised by a fitness instructor. Instead, when the exercycles are delivered, the participant will be shown how to use the exercycle and provided the exercise program as outlined above.
Patients will record their exercise program in an exercise diary, and it will include the length of training, the RPM, and the resistance setting.

To measure adherence, the Sirolimus (Rapamycin) will be blister-packed and the participants will complete an exercise diary. Both the medication packs and the exercise diary will be collected at the 6-week and 13-week intervals.
Intervention code [1] 323031 0
Prevention
Intervention code [2] 323032 0
Treatment: Drugs
Intervention code [3] 323033 0
Lifestyle
Comparator / control treatment
The 20 participants in the control group will also complete the 13-week, thrice-weekly, at-home exercise program, but will take a matching placebo instead of the Sirolimus (Rapamycin) once a week. The matching placebo will be manufactured by CompoundLabs
Control group
Placebo

Outcomes
Primary outcome [1] 330668 0
General muscle performance as measured by the 30-Second Chair-Stand Test (30CST)
Timepoint [1] 330668 0
The 30-Second Chair-Stand Test (30CST) will be measured at baseline and after 13 weeks post commencing treatment.
Secondary outcome [1] 407129 0
Handgrip strength as measured by a dynamometer
Timepoint [1] 407129 0
Measured at baseline and after 13 weeks post commencing treatment.
Secondary outcome [2] 407130 0
General fitness assessed by the 6-minute walk test
Timepoint [2] 407130 0
Measured at baseline and after 13 weeks post commencing treatment.
Secondary outcome [3] 407131 0
General balance assessed by the Community Balance & Mobility (CBM) scale
Timepoint [3] 407131 0
Measured at baseline and after 13 weeks post commencing treatment.
Secondary outcome [4] 407132 0
Lean muscle mass as measured by a DEXA scan
Timepoint [4] 407132 0
Measured at baseline and after 13 weeks post commencing treatment.
Secondary outcome [5] 407133 0
Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) as calculated via the blood glucose and insulin levels (glucose x insulin ÷ 22.5)
Timepoint [5] 407133 0
Measured at baseline and after 13 weeks post commencing treatment.
Secondary outcome [6] 407134 0
Full Blood Count
Timepoint [6] 407134 0
Measured at baseline and after 13 weeks post commencing treatment.
Secondary outcome [7] 407135 0
Renal functions tests (serum Creatinine, Sodium, Potassium)
Timepoint [7] 407135 0
Measured at baseline and after 13 weeks post commencing treatment.
Secondary outcome [8] 407136 0
Liver Function Tests - Serum Alanine transaminase (ALT), Alkaline phosphatase (ALP), Gamma-glutamyltransferase (GGT), Bilirubin, & Albumin
Timepoint [8] 407136 0
Measured at baseline and after 13 weeks post commencing treatment.
Secondary outcome [9] 407137 0
Serum Lipid Profile
Timepoint [9] 407137 0
Measured at baseline and after 13 weeks post commencing treatment.
Secondary outcome [10] 407138 0
Serum Insulin-like growth factor 1 (IGF-1)
Timepoint [10] 407138 0
Measured at baseline and after 13 weeks post commencing treatment.
Secondary outcome [11] 407139 0
DNA Methylation Clock (provided by TruDiagnostics) via blood sample
Timepoint [11] 407139 0
Measured at baseline and after 13 weeks post commencing treatment.
Secondary outcome [12] 409575 0
GlycanAge via blood sample
Timepoint [12] 409575 0
Measured at baseline and 13 weeks post commencing treatment
Secondary outcome [13] 410790 0
Quality of life assessed using the 36-Item Short Form Survey (SF-36)
Timepoint [13] 410790 0
Measured at baseline and at 13 weeks post commencing treatment.

Eligibility
Key inclusion criteria
• Males and females aged >=65 years and <=85 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, adherent, and agree to cooperate with all planned trial evaluations as explained in detail during the informed consent process and to be able to perform them.
Minimum age
65 Years
Maximum age
86 Years
Sex
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
• 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 12 months
• Any uncontrolled or serious disease, or anything 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 patient 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 or Type 2 Diabetes (HbA1c must be <50 mmol/mol)
• 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 patient 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

Study design
Purpose of the study
Prevention
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Phase 2
Type of endpoint/s
Efficacy
Statistical methods / analysis

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
5/02/2024
Actual
Date of last participant enrolment
Anticipated
5/08/2024
Actual
Date of last data collection
Anticipated
7/10/2024
Actual
Sample size
Target
40
Accrual to date
Final
Recruitment outside Australia
Country [1] 24639 0
New Zealand
State/province [1] 24639 0

Funding & Sponsors
Funding source category [1] 310941 0
Other Collaborative groups
Name [1] 310941 0
VitaDao
Country [1] 310941 0
Canada
Funding source category [2] 310942 0
Other Collaborative groups
Name [2] 310942 0
Lifespan.io
Country [2] 310942 0
United States of America
Primary sponsor type
Other Collaborative groups
Name
Vitality Healthspan Foundation
Address
3456 Paul Anka Drive. Ottawa, ON K1V 9K6
Country
Canada
Secondary sponsor category [1] 312234 0
None
Name [1] 312234 0
Address [1] 312234 0
Country [1] 312234 0

Ethics approval
Ethics application status
Not yet submitted
Ethics committee name [1] 310494 0
Health and Disability Ethics Committee
Ethics committee address [1] 310494 0
Level 1 South Tower, 110 Symonds Street, Grafton, Auckland 1010
Ethics committee country [1] 310494 0
New Zealand
Date submitted for ethics approval [1] 310494 0
05/03/2024
Approval date [1] 310494 0
Ethics approval number [1] 310494 0

Summary
Brief summary
Our brief hypothesis is that by having 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 Sirolimus (Rapamycin), this strategy will result in greater muscle performance in older adults compared with just exercise alone.

To explore this idea, we propose a 13-week, randomised, double-blind, placebo-controlled, Phase 2a Proof of concept trial of 40 participants, with 20 in the placebo arm and 20 in the Sirolimus (Rapamycin) arm. Participants will complete a thrice-weekly at-home exercise program. Medication will be taken once a week. Before the trial begins, exercycles will be delivered to the participant’s house, and once the trial begins the participants will complete a standardised exercycle program.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 117870 0
Dr Dr Brad Stanfield
Address 117870 0
Tuakau Health Centre
55 George Street, Tuakau, Auckland, 2121
Country 117870 0
New Zealand
Phone 117870 0
+64210426045
Fax 117870 0
Email 117870 0
brad@drstanfield.com
Contact person for public queries
Name 117871 0
Dr Dr Brad Stanfield
Address 117871 0
Tuakau Health Centre
55 George Street, Tuakau, Auckland, 2121
Country 117871 0
New Zealand
Phone 117871 0
+64210426045
Fax 117871 0
Email 117871 0
brad@drstanfield.com
Contact person for scientific queries
Name 117872 0
Dr Dr Brad Stanfield
Address 117872 0
Tuakau Health Centre
55 George Street, Tuakau, Auckland, 2121
Country 117872 0
New Zealand
Phone 117872 0
+64210426045
Fax 117872 0
Email 117872 0
brad@drstanfield.com

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Yes
What data in particular will be shared?
Anonymised patient result data, demographic data, exercise diary data, adherence to placebo/Sirolimus data
When will data be available (start and end dates)?
The data will be available after the trial is submitted to a clinical journal, and there will be no end date.
Available to whom?
The data will be available upon reasonable request
Available for what types of analyses?
Meta-analysis and auditing
How or where can data be obtained?
Contact the trial co-principle investigator at brad@drstanfield.com


What supporting documents are/will be available?

Doc. No.TypeCitationLinkEmailOther DetailsAttachment
15305Study protocol    383703-(Uploaded-25-03-2022-05-47-00)-Study-related document.pdf



Results publications and other study-related documents

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No documents have been uploaded by study researchers.

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