Title: Leucine and ACE inhibitors as therapies for sarcopenia: a two by two factorial randomised placebo controlled trial
Funder: Chief Scientist Office, Scotland

Abstract: Hypothesis and aims: We hypothesise that supplementation with the essential amino acid leucine and/or angiotensin converting enzyme inhibitor (ACEi) therapy will improve phy muscle mass and function in older people with sarcopaenia. Leucine supplementation has been shown to counter the resistance to muscle protein synthesis in older people, reduce inflammatory markers, improve insulin resistance, increase satellite cells (indicating muscle regeneration) and improve mitochondrial function in muscle. ACEi (a common cardiovascular medication) has been shown to reduce inflammatory cytokines and myokines, improve insulin resistance and mitochondrial function in skeletal muscle. We have previously found that ACEi improves exercise capacity (equivalent to that seen after 6 months of exercise training) in older people. While both interventions can positively affect many factors implicated in the development of sarcopenia their effect has not been tried in this group. We will study the effect of leucine and ACEi on muscle performance and muscle mass in sarcopenia. Further we will investigate biomarkers which predict response to interventions and examine mechanisms of action of these interventions on sarcopaenia. Design: Multicentre double blind randomised controlled 2x2 factorial trial Population: >/=70 years with sarcopaenia as per the EWGSOP definition (loss of both muscle mass and function). Excluding those on or with contraindications to ACEi Interventions: 4 groups receiving one of perindopril+leucine, perindopril+placebo, leucine+placebo or placebo+placebo for 12 months. Leucine dose will be 2.5g, 3 times/d and perindopril will be 4mg/day. Outcomes: Primary outcome is the difference in Short Physical Performance Battery between leucine vs.placebo and perindopril vs placebo. Secondary outcomes are change in muscle mass, grip strength, quadriceps strength, 6 minute walking distance, quality of life (EuroQol) Assessments: Performed at baseline, 6 and 12 months. Safety assessments will be done 3 monthly. Sample size: 440 participants (n=110 per group) will have 90% power at 0.05 alpha to identify a change of 0.5 (SD 2.7) in primary outcome allowing for a 20% drop out rate. Statistical analysis: Change in outcome measures between interventions will be analysed using repeated measures using mixed modelling. Economic benefit: Sarcopaenia is a major contributor to loss of mobility, falls, institutionalisation, morbidity and mortality in older people. Both leucine and perindopril are inexpensive. If found to be acceptable for older people and effective in improving sarcopaenia, these agents will be value for money, costing less than a £300 per patient per year. Duration of study – 42 months. Estimated recruitment of 2 participants/month from 15 sites in frail older people. Main stages of proposed project -9 to 0 months Regulatory approvals 0-3 months Train personnel 4-22 months Recruitment 16-34 months Final visit, Biomarker analyses commences 35-42 months Biomarker analyses, data analysis, report writing Biomarker substudy: Blood will be analysed for biomarkers that predict improvement in muscle mass and function. Changes in microRNA, myokines, cytokines and hormones in blood, plus selected gene polymorphisms will be measured to examine predictors of response to therapies and changes in biological pathways in sarcopenia in response to interventions.

Lay abstract: Sarcopenia, the loss of muscle that occurs with advancing age, is a major contributor to immobility, falls, nursing home admissions and death. Exercise is the mainstay of attempts to minimise its impact but many older people are unwilling or unable to do adequate exercise. Non-exercise approaches to reduce sarcopenia are required urgently. Two potential medical treatments show promise: leucine and angiotensin converting enzyme inhibitor (ACEi) drugs. Leucine, a natural component of proteins, is known to improve certain body pathways that can lead to sarcopaenia. Protein in food helps build protein in muscles, but unlike younger adults, older adults need larger amounts of leucine before they can build up protein in muscles. Moreover many older adults do not eat enough protein and are reluctant to take large volumes of protein supplements. Increasing leucine intake increases muscle protein build up even when less protein is consumed. Therefore leucine may be the stimulus required to build stronger muscles and to counter sarcopenia. ACEi are commonly used medicines for managing heart trouble. Our previous research showed that use of ACEi drugs in older people with mobility problems improved their ability to exercise just as much as 6 months of exercise training would have done. We predict that ACEi will also benefit people with sarcopenia. Neither leucine nor ACEi have previously been tested in older people with sarcopenia. We will study the effect of leucine and the ACEi drugs for 1 year with older adults with sarcopenia. We will include 440 people >=70years (people most likely to have sarcopenia and commonly excluded from research) with sarcopenia from around 15 centres associated with the NHS in the UK. We will measure changes in physical ability: walking speed, time taken to do 5 chair stands, balance, muscle strength, distance walked in 6 minutes and quality of life. Change in muscle size will be measured using DEXA scans (similar to X-rays).Blood tests will be analysed to find out how the two interventions work and for indicators (biomarkers) to help us target which people are likely to respond best to treatment. Both leucine and ACEi drugs are well tolerated in older people. We will monitor closely for side effects and no major ethical issues are anticipated. Our team has a proven track record in conducting clinical trials with older adults, including multicentre trials, analysing blood and muscles in people with muscle wasting, statistical expertise and support from a Clinical Trials Unit The costs requested are essential for managing the study to highest standards. The major costs cover a Trial Manager to oversee the study, time for a research nurse and doctor at each study site; manufacture of medicines and placebo; taxi fares for participants (essential for supporting older people take part in research); biomarker analysis by a post-doctoral scientist. Costs for scans and equipment (bioimpedance scan for screening to save on DEXA scans, hand grip and knee strength dynamometers), consumables and Clinical Trials Unit input. NHS support costs will provide research support from NIHR networks and tests to ensure safety of participants.

Research activity codes: 6.1 PHARMACEUTICALS
Health categories: MUSCULOSKELETAL