Exercise and Nutrition for Healthy AgeiNg

Study Overview
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Brief Summary
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The aim of this randomized placebo-controlled 5-arm clinical trial is to evaluate the effect of combined anabolic interventions compared to single or placebo interventions on physical performance in community-dwelling (pre)sarcopenic elderly (≥ 65 years) and to determine the underlying mechanisms of action. Important secondary outcome measures are muscle mass, muscle strength, compliance to the interventions (exercise program, protein and omega-3 supplementation) and functional, cognitive and nutritional status.

Detailed Description
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The aim of this randomized 5-arm clinical trial is to evaluate the effect of combined anabolic interventions compared to single or placebo interventions on physical performance in community-dwelling (pre)sarcopenic elderly (≥ 65 years) living in Belgium. Physical performance will be evaluated using the Short Physical Performance Battery (SPPB). Muscle mass will be measured using a dual energy x-ray absorptiometry (DXA) and/or bioelectrical impedance analysis (BIA). Muscle strength will be measured by the Biodex (knee-extensor and knee-flexor) and a 1 hand-held dynamometer. The trial will also determine the underlying mechanisms of action using blood measures (such as markers of inflammation and sarcopenia) and muscle biomarkers. Important secondary outcome measures are compliance to the exercise program and to the protein and omega-3 supplementation, as well as functional, cognitive and nutritional status and the patients report on benefits and adverse events. The study consists of four parts. Part I is the screening phase, which starts from the moment the participant has signed the informed consent until the start of the preparations of the study. During the screening, participants will be assessed for study eligibility by the study coordinator and contributors. If the participant is eligible, he or she will be randomly assigned into 1 of 5 intervention groups: Group 1: Exercise intervention; Group 2: Protein supplement; Group 3: Exercise intervention + protein supplement; Group 4: Exercise + Protein supplement + omega-3 supplement; Group 5: No intervention. Part II is the preparation phase, in which the participants starts some of the interventions before the start of the study to familiarize patients with e.g. the intake of a protein supplement. All the participants will take an oral vitamin D supplement (800 IU cholecalciferol) from 4 weeks before the start of the intervention if their vitamin D level is above 20 nmol/L. Patients with a vitamin D level < 20 nmol/L will receive repletion therapy. A trial diary will be completed by all participants to record PA, falls and intake of protein/omega3/placebo and vitamin D products. Participants in the exercise intervention (group 1, 3 and 4) will be invited to an information session where the Otago Exercise Program (OEP) will be explained and practiced. With respect to the protein supplementation, participants will receive an individually adapted protein supplement to achieve the recommended total daily intake of 1.5 g protein/kg. This will be realized by adding an individualized amount (g) of protein powder during breakfast, lunch, dinner or snack between, before or after meals, based on the subjects' food intake assessed by a food diary. The protein powder is commercially available and consists of 4.5g protein/ 5g powder. The participants in group 2, 3 and 4 will start taking the protein supplement or matched placebo 5 days before the start of the intervention. Four weeks before the start of the intervention, the participants of group 4 will start with the intake of omega-3 (1 capsule providing in total 500 mg eicosapentanoic acid (EPA) and 450 mg docosahexaenoic acid (DHA)) or matched placebo. Placebo will be provided for the participants who are not given a protein and/or omega-3 supplement. Participants are blinded to the nutritional interventions. The third part of the study, the intervention period, takes 12 weeks. During this period, there are 8 contact moments (at baseline, week 1, week 2, week 4, week 6, week 8, week 10 and week 12). All the participants continue with the vitamin D supplementation. Participants in the exercise intervention (group 1, 3 and 4) will perform the optimized and personally adapted OEP and will also follow a walking plan. The strength exercises of the OEP are personalised based on the individual's 1 repetition maximum. Balance exercises of the OEP are personalised based on improvements on MiniBESTest scores during the intervention period. The nutritional intervention groups (protein supplementation: group 2, 3 and 4 and omega-3 supplementation: group 4) continue with the protein and/or omega-3 supplements until the last visit of the intervention period. Part IV is the follow-up period, after the intervention. This phase takes 12 weeks and exists of 2 telephone contacts and 2 contact moments. All the participants continue the vitamin D supplementation until the last visit of the follow-up. The exercise intervention group (group 1, 3 and 4) may continue the OEP, but no personal encouragement will be given during this period. No protein and/ or omega-3 supplements will be given during the follow-up. Several outcomes will be measured during the contact moments of the intervention period and follow-up period (part III and part IV). This will be done by questionnaires about nutritional status, fall history and use of health care (from baseline until end of follow-up), and evaluation of functional and cognitive status. Blood, urine and muscle samples will be taken. The physical activity will be measured by wearing a movement tracker. All participants will wear a movement tracker 5 days before the intervention period and during the first two weeks of the intervention period and last two weeks of the intervention period, and during the last 2 weeks of the follow-up period. Participants who receive an exercise intervention (group 1, 3 and 4) will be encouraged to wear the movement tracker during the complete intervention period. The participants will complete a four-day food diary throughout the trial at week 1, week 6, week 12 and week 24. The participants will be asked for compliance during the preparation period and intervention period and their fall history which can be monitored by using diaries during the intervention period and the follow-up period. Addendum 27-07-2021: starting from 01-2021 a substudy was initiated in which participants of ENHANce, who agreed for participation in this substudy, collect stool samples at baseline, week 4, week 8 and week 12 of the intervention. This will allow to observe possible changes in gut microbiota composition and intestinal inflammation.

Official Title
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Exercise and Nutrition for Healthy AgeiNg: Anabolic Interventions for Older People With (Pre)Sarcopenia to Improve Physical Functioning, Muscle Mass and Muscle Strength and to Understand the Underlying Mechanisms of Action.

Conditions
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Sarcopenia

Intervention / Treatment
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* Behavioral: Home-based training program
* Dietary Supplement: High-quality protein supplement
* Dietary Supplement: Omega-3 fatty acid
* Drug: Placebo protein powder
* Drug: Placebo omega-3


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female persons with (pre)sarcopenia according to the European Working Group on Sarcopenia in Older People (EWGSOP): reduced muscle mass without (presarcopenia) or with (sarcopenia) reduced walking speed (≤ 0.8m/s) or muscle strength OR probable, confirmed or severe sarcopenia according to EWGSOP 2. 65 years or older; Community-dwelling elderly or assisted living; In case of one or more positive answer(s) on the health screen for exercise, subjects need approval of their general practitioner to participate in this randomized controlled trial (RCT). Uncontrolled or unstable health problems Uncontrolled pain or feeling unwell the day of the exercise Recently diagnosed cardiovascular events systolic blood pressure (SBP) ≥ 180 mmHg and/or diastolic blood pressure (DBP) ≥ 100 mmHg Resting tachycardia > 100 bpm Uncontrolled atrial or ventricular arrhythmias Unstable or acute heart failure Lasting, increased pain following a previous session Suspected acute injury Recent injurious fall without medical assessment Severe breathlessness or dizziness Uncontrolled pulmonary problems Rheumatoid arthritis flare up or acute systemic illness/infection Unexplained lethargy Exclusion Criteria: Impairments/diseases that impose problems to participation in the study; Allergy to milk or soy or peanut; Mini-Mental State Examination (MMSE) < 21; Terminal illness (prognosis < 6 months); Persons who followed a physical training program in the last 6 months (twice or more/week); Persons with a daily intake of > 1.5 g protein/kg body weight (BW)/day; Diagnosis of severe kidney disease (GFR < 30 ml/min) or diabetes mellitus; Unable to communicate in Dutch, English or French.

Ages Eligible for Study
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Minimum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Home-based training program<br>Home-based training program + protein placebo + omega-3 placebo | Behavioral: Home-based training program<br>* Exercise intervention: During the intervention period, the participant will perform the optimized and personally adapted Otago Exercise Program (OEP). The participant is encouraged to perform the resistance exercises three times a week with a rest day in between. The participant is advised to perform the exercises in close temporal proximity to one of the moments of the intake of the protein supplement. The participant will also follow a walking plan in which he or she needs to walk 30 minutes twice a week. These 30 minutes can be broken down to three 10-minute walks throughout the day. During the follow-up period, participants may continue the OEP, but no personal encouragement will be given during this period.<br>Drug: Placebo protein powder<br>* Isocaloric maltodextrin powder. Amount based on food diary.<br>Drug: Placebo omega-3<br>* Peanut oil soft gel capsules. 1g/ capsule. 1 capsule/day<br>|
| Experimental: High-quality protein supplement<br>High-quality protein supplement + omega-3 placebo | Dietary Supplement: High-quality protein supplement<br>* The participant will receive an individually adapted protein supplement to achieve the recommend total (usual diet and supplements) daily intake of 1.5 g/protein/kg for frail elderly. This will be realized by adding an individualized amount (g) of protein powder during breakfast, lunch, dinner or snack between meals, or before breakfast or after dinner, based on the subjects' food intake assessed by a food diary. The participant will take the protein supplement from 5 days before the start of the intervention. The protein powder is commercially available and consists of 4.5g protein/5g powder. During the follow-up, no protein supplement is added.<br>Drug: Placebo omega-3<br>* Peanut oil soft gel capsules. 1g/ capsule. 1 capsule/day<br>|
| Experimental: 2 Anabolic interventions<br>Home-based training program and high quality protein supplement | Behavioral: Home-based training program<br>* Exercise intervention: During the intervention period, the participant will perform the optimized and personally adapted Otago Exercise Program (OEP). The participant is encouraged to perform the resistance exercises three times a week with a rest day in between. The participant is advised to perform the exercises in close temporal proximity to one of the moments of the intake of the protein supplement. The participant will also follow a walking plan in which he or she needs to walk 30 minutes twice a week. These 30 minutes can be broken down to three 10-minute walks throughout the day. During the follow-up period, participants may continue the OEP, but no personal encouragement will be given during this period.<br>Dietary Supplement: High-quality protein supplement<br>* The participant will receive an individually adapted protein supplement to achieve the recommend total (usual diet and supplements) daily intake of 1.5 g/protein/kg for frail elderly. This will be realized by adding an individualized amount (g) of protein powder during breakfast, lunch, dinner or snack between meals, or before breakfast or after dinner, based on the subjects' food intake assessed by a food diary. The participant will take the protein supplement from 5 days before the start of the intervention. The protein powder is commercially available and consists of 4.5g protein/5g powder. During the follow-up, no protein supplement is added.<br>Drug: Placebo omega-3<br>* Peanut oil soft gel capsules. 1g/ capsule. 1 capsule/day<br>|
| Experimental: 3 Anabolic interventions<br>Home-based training program, high-quality protein supplement and omega-3 fatty acids | Behavioral: Home-based training program<br>* Exercise intervention: During the intervention period, the participant will perform the optimized and personally adapted Otago Exercise Program (OEP). The participant is encouraged to perform the resistance exercises three times a week with a rest day in between. The participant is advised to perform the exercises in close temporal proximity to one of the moments of the intake of the protein supplement. The participant will also follow a walking plan in which he or she needs to walk 30 minutes twice a week. These 30 minutes can be broken down to three 10-minute walks throughout the day. During the follow-up period, participants may continue the OEP, but no personal encouragement will be given during this period.<br>Dietary Supplement: High-quality protein supplement<br>* The participant will receive an individually adapted protein supplement to achieve the recommend total (usual diet and supplements) daily intake of 1.5 g/protein/kg for frail elderly. This will be realized by adding an individualized amount (g) of protein powder during breakfast, lunch, dinner or snack between meals, or before breakfast or after dinner, based on the subjects' food intake assessed by a food diary. The participant will take the protein supplement from 5 days before the start of the intervention. The protein powder is commercially available and consists of 4.5g protein/5g powder. During the follow-up, no protein supplement is added.<br>Dietary Supplement: Omega-3 fatty acid<br>* Four weeks before the start of the intervention, the participant will start the intake of 1 omega-3 capsule providing in total 500 mg EPA and 450 mg DHA until the end of the intervention. He or she has to take the supplement once daily at a chosen time. During the follow-up, no omega-3 supplement will be given.<br>|
| Placebo Comparator: Placebo protein powder and omega-3<br>Control group: protein placebo + omega-3 placebo | Drug: Placebo protein powder<br>* Isocaloric maltodextrin powder. Amount based on food diary.<br>Drug: Placebo omega-3<br>* Peanut oil soft gel capsules. 1g/ capsule. 1 capsule/day<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in physical functioning | Change in SPPB score | Measured at baseline, week 12 and week 24. | 
| Percentage of participants with change in physical functioning | the percentage of participants with more than 1 or 1 point increase in SPPB score. | Measured at baseline, week 12 and week 24. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in muscle mass (after intervention-baseline) | Appendicular lean mass will be measured with a whole-body DXA scan and by BIA. | Measured at screening, week 12 and week 24 with DXA or when screening is 6 weeks prior to baseline, DXA will also be performed at baseline. At screening, baseline, week 12 and week 24 with BIA. | 
| Change in muscle strength (after intervention-baseline) | Muscle strength of the knee-extensor, knee-flexor and hip abductors will be measured by Biodex and hand grip strength with dynamometer. | Hand grip measured at screening, baseline, week 12 and week 24. Biodex measured at baseline, week 12 and week 24. | 
| Compliance to the exercise intervention, subjective | Compliance to the Otago program will be assessed by measure of: - The number of Otago sessions the participant performed divided by the number of Otago sessions the participants needed to perform. Likewise, this will be calculated for the walking program and for the integral exercise intervention. | baseline until week 12 | 
| Compliance to the exercise intervention, objective | Compliance to the Otago program will be assessed by measure of: - Monitor and diary: Length of exercise session (time). Pattern recognition of exercise groups by algorithm development | baseline until week 12 | 
| Compliance to the exercise intervention, subjective, detailed | Compliance to the Otago program will be assessed by measure of: - Diary: the reported intensity of the strength exercises | baseline until week 12 | 
| Compliance to the protein supplementation, objective | Compliance to protein supplementation: - The number of nutritional intakes the participant did divided by the number of intakes of nutritional supplement the participant was prescribed. | Urine samples at baseline, week 1, 2, 4, 6, 8, 10, 12, 24. | 
| Compliance to the protein supplementation, subjective | Compliance to protein supplementation: - Count and weight returned powder boxes | Urine samples at baseline, week 1, 2, 4, 6, 8, 10, 12, 24. | 
| Compliance to the protein supplementation objective | Compliance to protein supplementation: - N content in 8 24h urine samples by the Dumas method (28) to estimate rise in protein intake and Creatinine index to estimate the completion of the urine samples (29, 30) | Urine samples at baseline, week 1, 2, 4, 6, 8, 10, 12, 24. | 
| Compliance to the omega-3 supplementation, subjective | Compliance to omega-3 supplement - Count returned capsules and placebo tablets | baseline, week 12 and week 24. | 
| Compliance to the omega-3 supplementation, objective | Compliance to omega-3 supplement - Compliance to the omega- 3 supplement is assessed by counting the number of capsules during each study visit and by analysis of red blood cell (RBC) membrane fatty acid profile | baseline, week 12 and week 24. | 
| Functional status: frailty | - Change in physical frailty stage defined by Fried et al (frail (3-5/5), prefrail (1-2/5), robust (0/5)) | baseline, week 12 and 24 | 
| Functional status: activities of daily living | Change in activity of daily living (ADL) :Barthel-index | baseline, week 12 and 24 | 
| Functional status: balance | Change in balance (Mini-BESTest) | baseline, week 12 and 24 | 
| Functional status: change in physical activity | Change in PA by the MoveMonitor+ (MM+) (method under development in our research group) | baseline, week 12 and 24 | 
| Functional status: health-related quality of life | - Change in health-related quality of life, according to Short Form Health Survey (SF-36) questionnaire | baseline, week 12 and 24 | 
| Functional status: falls | - Number of falls and the circumstances, identified using weekly fall calendars + Falls Efficacy Scale International (FES-I) | baseline, week 12 and 24 | 
| Cognitive status: immediate and delayed memory, attention, language and visuospatial skills | - The Repeatable Battery for the Assessment of Neuropsychological Status (RBANS): immediate and delayed memory, attention, language and visuospatial skills; | baseline, week 12 and 24 | 
| Cognitive status: inhibition | Stroop test (inhibition) | baseline, week 12 and 24 | 
| Cognitive status | - Maze test | baseline, week 12 and 24 | 
| Nutritional status: malnutrition | - Changes in numbers of participants with malnutrition, according to Mini Nutritional Assessment (MNA). | at baseline (preparation for food diary), week 6, week 12 and week 24 | 
| Nutritional status: nutrient intake | - Changes in nutrient intake, according to the four day food diary. | at baseline (preparation for food diary), week 6, week 12 and week 24 | 
| Patient reported benefits and adverse effects | Benefits and adverse effects are asked. Participants will describe their thoughts about the study, what they like and don't like. | week 1, 4, 8, 12, 16, 20, 22, 24. | 
| Change in C reactive protein (CRP) | change in hs-CRP | baseline, week 1, 4, 12 and 24 | 
| Change in hemoglobin | Change in hemoglobin | baseline, week 12 and week 24 | 
| Change in creatinine | Change in creatinine | baseline, week 12 and week 24 | 
| Change in urea | Change in urea | baseline, week 12 and week 24 | 
| Change in serum albumin | Change in serum albumin | baseline, week 12 and week 24 | 
| Change in glucose | Change in glucose | baseline, week 12 and week 24 | 
| Change in cholesterol (HDL, LDL, total, Triglycerides) | Change in cholesterol (HDL, LDL, total, Triglycerides) | baseline, week 12 and week 24 | 
| Change in insulin | Change in insulin | baseline, week 12 and week 24 | 
| Change in insulin like growth factor 1 (IGF-1) | Change in IGF-1 | baseline, week 12 and week 24 | 
| Change in 25-hydroxy-vitamin D | Change in 25-hydroxy-vitamin D | baseline, week 12 and week 24 | 
| Change in creatinine kinase | Change in creatinine kinase | baseline, week 12 and week 24 | 
| Change in indoxyl sulfate | Change in indoxyl sulfate | baseline, week 12 and week 24 | 
| Change in interleukin 6 (IL-6) | Change in IL-6 | baseline, week 12 and week 24 | 
| Change in IL-1b | Change in IL-1b | baseline, week 12 and week 24 | 
| Change in tumor necrosis factor alpha (TNF-alpha) | Change in TNF-alpha | baseline, week 12 and week 24 | 
| Change in myostatin | Change in myostatin | baseline, week 12 and week 24 | 
| Change in activin A | Change in activin A | baseline, week 12 and week 24 | 
| Change in markers of muscle wasting | Change in markers of muscle wasting (MURF1, Atrogin1, FOXO3) | baseline, week 12 | 
| Change in markers of muscle regeneration | Change in markers of muscle regeneration (PAX7, Myogenic factor 5 (MYF5), myoblast determination protein (MyoD), Ki67, mammalian target of rapamycin (mTOR), AMPK) | baseline, week 12 | 
| Change in muscle histology | Change in muscle histology | baseline, week 12 | 
| Change in composition of gut microbiota | Change in composition of gut microbiota | baseline, week 4, week 8, week 12 | 
| Change in markers of intestinal inflammation | Change in markers of intestinal inflammation (fecal calprotectin, lactoferrin, S100A12) | baseline, week 4, week 8, week 12 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Sarcopenia, Nutrition, Protein, Vitamin D, Exercise, Older people, Frailty