S T U D Y P R O T O C O L Open Access
Effects of β-hydroxy-β-methylbutyrate
(HMB) supplementation in addition to
multicomponent exercise in adults older
than 70 years living in nursing homes, a
cluster randomized placebo-controlled trial:
the HEAL study protocol
, JG Pallarés and on behalf of the HEAL study group
Background: Evidence supports the fact that multicomponent exercise and HMB supplementation are, separately,
effective in improving older adult’s health and palliate functional metabolic diseases in older people. However, the
true effect of HMB supplementation combined with a tailored exercise program in frail older adults is still unknown.
Thus, the aim of the HEAL (HMB + Exercise = Adults Living longer) study is to assess the effects of the combination
of a daily multicomponent exercise and resistance training (VIVIFRAIL program) intervention in addition to HMB
supplementation on older adults’health.
Methods/design: A 24-week cluster randomized, double-blind, placebo-controlled study will be conducted on 104
adults ≥70 years. Nursing homes will be randomized to either of four groups: Ex-HMB (exercise intervention with
HMB), Ex-Plac (exercise intervention with placebo), NoEx-HMB (no exercise intervention with HMB), and Controls
(No exercise and no HMB). Intervention groups which include exercise will complete the individualized
multicomponent (strength, balance and cardiovascular exercises) training program VIVIFRAIL. Intervention groups
which include HMB supplementation will receive a 3 g/daily dose of free acid HMB in powder form. The primary
outcome measure is the functional capacity. Secondary outcome measures are muscle strength and power, frailty
and fall risk, body composition, biochemical analyses and cardiometabolic risk factor, disability and comorbidity,
cognitive function and depression.
Discussion: The findings of the HEAL study will help professionals from public health systems to identify cost-
effective and innovative actions to improve older people’s health and quality of life, and endorse exercise practice
in older adults and people living in nursing homes.
Trial registration: NCT03827499; Date of registration: 01/02/2019.
Keywords: Healthy ageing, Physical activity, Physical fitness, Falls, Dynapenia
© The Author(s). 2019 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0
International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and
reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to
the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver
(http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
* Correspondence: Javier.email@example.com
Human Performance and Sports Science Laboratory, Faculty of Sport
Sciences, University of Murcia, Calle Argentina, 19, 30720 San Javier, Murcia,
Courel-Ibáñez and Pallarés BMC Geriatrics (2019) 19:188
To date, people are living more years than ever before in
history and the world’s aging is rising at a staggering rate
. Thus, strategies focused on health maintenance for
aging people through exercise and proper nutrition are
required to contribute to lifelong wellbeing and prevent
ageing diseases and chronic illness. Frailty, sarcopenia,
dynapenia and sarcopenic obesity states are the main
metabolic complications in older people and represent a
major public health challenge [2–4]. A recent estimation
from the Eurostat online database (28 European countries)
suggests increments from 60 to 70% of individuals with
sarcopenia in 2045 affecting 12.9 to 22.3% of people over
65 years old . These diseases are caused by a degenera-
tive loss of muscle mass (muscle wasting), strength and
mobility. The combination of exercise with protein dietary
supplementation is proven to be highly effective to in-
crease muscle mass and strength in older adults [6–8].
Evidence states that exercise in older people is a main
component in frailty prevention (increases strength and
decreases falls incidence) and functional capacity preserva-
tion (increases mobility and autonomy) [8–10]. In turn,
weak elders have greater risk of disability, hospitalization,
morbidity and death [3,11]. In addition to a better phys-
ical condition, exercise has a clear impact on psychological
well-being in older people . Although much remains
to be done, the possibility of physical exercise as the new
medication for the twenty-first century is truly inspiring.
The first step of this revolution is that the question is
turning from “may I prescribe physical activity for older
people?”to “what kind of exercise must I prescribe?”.
Reducing sedentary behaviours and promoting exercise
training in older adults living in nursing homes stands as a
main global challenge [14,15].
Very recently, the ERAMUS+ co-funding VIVIFRAIL
project (http://www.vivifrail.com) has developed a multi-
component exercise program (strength, balance and car-
diovascular exercises), carefully adapted, for improving
functional capacity for older people above 70 years .
The program includes a practical guide for testing and
prescribing the physical training according to each spe-
cific condition (serious, moderate, slight or no limitation,
and with or without risk of falling). Furthermore, the
VIVIFRAIL App allows individuals’monitoring and pro-
vides clear instructions to effectively complete the pro-
gram within the everyday environment. Now that long-
term exercise interventions in older adults are more pos-
sible than ever , what is now required is to examine
the effectiveness of this program on relevant health and
functional outcomes for older adults and nursing homes
The β-hydroxy-β-methylbutyrate (HMB) dietary is a
bioactive metabolite formed from the decomposition of
leucine, an essential branched-chain amino acid. The
importance of leucine has anti-catabolic properties and
plays an important role in protein metabolism, glucose
homeostasis, insulin action and recovery from exercise
[18–20]. A dose of 3 g of HMB dietary supplementation
provides 60 g of leucine, which otherwise would imply
600 g of high biological value protein . The HMB
supplementation is affordable (around 50€/kg) and its
consumption is safe with no adverse effects [22,23]. In
older adults > 60 years old, HMB is demonstrated to
have anti-catabolic effect, enhance protein synthesis, at-
tenuate proteolysis, increase muscle mass and decrease
muscle damage [24–26]. Despite the fact that HMB effi-
cacy varies , a meta-analysis concluded that HMB
supplements contribute to the preservation of muscle
mass in old age . Based on these findings, the sup-
plementation of HMB appears to be an effective strat-
egy to prevent metabolic and physical complications in
ageing (frailty, dynapenia, sarcopenia and sarcopenic
obesity) and preserve health, functional capacity and
strength in older people.
A recent investigation  reported for the first time a
significant reduction of 50% in whole body plasma con-
centration of HMB and reductions of 25% on the conver-
sion of leucine to HMB in older adults (~ 65 y-old). At the
moment, there is limited understanding why this happens,
but it seems clear than reductions in HMB conversion are
associated with age . These decrements on high qual-
ity protein synthesis importantly accounted for a decline
in muscle weakness in older people . Hence, the possi-
bility of palliating muscle and functional losses in the age-
ing by HMB supplementation is truly inspiring and
encourages further studies [26,27].
To date, only five Randomized Control Trial (RCT)
studies have examined the effectiveness of exercise train-
ing combined with HMB dietary supplementation in
older adults > 60 years old [31–35]. Whereas it seems
clear that HMB supplements contribute to the preserva-
tion of muscle mass in old age, contradictory evidence
on its effects on strength increments [31–34] and func-
tional performance [33–35] in older adults exists. These
equivocal outcomes may be attributed to the protocols
applied, with discrepancies in the training volume (num-
ber of sessions, time per session, number of reps), inten-
sity (load monitoring and progression) and exercises.
Besides, sample sizes explored are reduced (n< 32)
and only one RCT  conducted an exercise inter-
vention > 8 weeks. Consequently, there is a need for
longer and larger studies to fully determine the potential
effects of HMB supplementation on physical performance,
translating to a functional benefit . In this sense, the
HEAL (HMB + Exercise = Adults Living longer) study will
be the first RCT conducting a specific, individualized,
multicomponent exercise intervention for the older adult
population such as the VIVIFRAIL . Because this
Courel-Ibáñez and Pallarés BMC Geriatrics (2019) 19:188 Page 2 of 10
evidence-based program has been proven as effective and
safe in adults aged 65 years or over , it represents an
excellent opportunity to determine the true effects of
HMB supplementation in enhancing training perform-
ance. Furthermore, the promising results of HMB sup-
plementation to mitigate age-related cognitive deficits
[36,37] and the lack of studies exploring its impact on
people with very limited or no mobility [25,38]encourage
adopting this strategy in vulnerable people such as older
nursing homes patients. Therefore, the aim of the HEAL
study is to assess the effects of the combination of a daily
multicomponent exercise and resistance training (VIVIF-
RAIL program) in addition to HMB supplementation on
Study design and settings
This is a cluster randomized, placebo-controlled study
with four parallel groups. The study has been designed
to determine the efficacy of HMB supplementation in
addition to 24-weeks of multicomponent exercise and
resistance training (the VIVIFRAIL program) in adults
≥70 years. Flowchart of the trial is shown in Fig. 1.
Enrollment, intervention allocation, follow-up, and data
analysis will be conducted according to the SPIRIT
(Standard Protocol Items: Recommendations for Inter-
ventional Trials) statement [39,40].
Inclusion criteria for enrollment will be: men and
women aged ≥70 years, be able to follow an active phys-
ical rehabilitation program and voluntary participation.
Enrollment of cognitively impaired older adults will re-
quire proxy permission (family member or caregiver)
. All potential participants will provide a medical
history and undergo a medical examination to identify
cardiovascular or metabolic conditions that would ex-
clude participation (for full list, see Table 1).
The required sample size will be determined on the basis
on the functional capacity, using the Short Physical Per-
formance Battery (SPPB) . According to previous re-
search on subjects with similar characteristics , a
clinically relevant change is about 1.5 ± 1.0 points incre-
ments after 12-weeks. Differences of 2 point in total SPBB
Fig. 1 Flowchart of the trial
Courel-Ibáñez and Pallarés BMC Geriatrics (2019) 19:188 Page 3 of 10
with a standard deviation of 3 points with a power of 80%
and αof 0.05 can be estimated with 20 participants using
the R software (v. 3.2.1) and the package samplesize.As-
suming a maximum loss of follow-up of 30%, we will re-
cruit 26 adults ≥70 years per group (n= 104). Similar
interventions had an adherence rate of 75%, and a mean
attendance of 80% to the sessions . Therefore, the
current estimation is realistic and affordable.
Recruitment process and measurements procedures
A schematic overview of the outcomes, measures and
timeline is shown in Table 2. Recruitment will be carried
out in nursing homes in Murcia (Spain) located within a
radius of 15 km or less than 20 min by car from the assess-
ment sites. There are over 15 nursing homes among this
radius that ensure recruitment of enough participants. Ini-
tial assessment will be carried out in the Human Perform-
ance & Sports Science Lab, Faculty of Sport Sciences,
University of Murcia (Murcia, Spain). Body composition
and biochemical analyses will be performed in the Medical
Centre Virgen de la Caridad (Murcia, Spain). Participants
will be scheduled in small groups to be taken to the
laboratory for the initial assessment and medical centre.
Dependent people will be transported in adapted vehicles
with a caregiver. All measurements will be performed
under technical and medical supervision.
The VIVIFRAIL exercise program will be administered
by a training team (experienced and qualified personal
trainers and physical therapists), under nursing supervi-
sion. After the initial assessment and one week before
the start of the intervention, participants will attend a
familiarization session at the place in which the testing
and training will be conducted.
Randomization and blinding
After recruitment and baseline measurements, nursing
home will be randomized to either of the four groups in
clusters, according to a computer-generated sequence
using the Sealed Envelope Ltd. online system. The clus-
ter design is chosen to prevent influences on partici-
pants’behaviours within a given nursing home unit. A
stratified randomization will be used according to their
initial functional status (A, B, C or D, see Fig. 2) to re-
duce imbalance between groups. The allocation will be
concealed in a password protected computer file. Given
the nature of the treatment (i.e., daily exercise and diet-
ary supplementation program), participants will be aware
of their group allocation. Outcome assessors and data
analysts will be blinded to the treatment group assign-
ment. Assessors will not be involved in intervention ac-
tivities. A dedicated protocol will be defined to protect
the confidentiality of data.
Intervention groups including HMB supplementation
(Ex-HMB and NoEx-HMB) will receive a 3 g daily dose
of free acid HMB in powder form (myprotein.co.uk,
Cheadle, Cheshire, UK) dissolved freely into 250 mL of
water during a 24-week intervention [34,43]. Nursing
staff will supply the doses as a part of their daily diet
routine. Ex-Plac and Control groups will receive stevio-
side. Supplements will be packaged in indistinguishable
envelopes and boxes, with an identification code for each
participant and group. The compliance of supplementa-
tion will be monitored and ensured by medical staff
working at the nursing home. Oral supplement and
Vitamin D will be provided to maintain an acceptable
Multicomponent physical exercise program
Intervention groups including exercise (Ex-HMB and
Ex-Plac) will complete an individualized multicompo-
nent training program, VIVIFRAIL , 5 days a
week during 24 weeks. Free on-line resources and
program guidelines are available online (http://www.
vivifrail.com/resources). The VIVIFRAIL program has
been carefully designed for people ≥70 years and in-
cludes six programs or “Passports”adapted for each
participant’s condition according to their functional
limitation (serious [A], moderate [B], slight [C] and
no limitation [D]) and risk of falling (B+ and C+).
Individualization is made based on the baseline test-
ing scores (i.e., the VIVIFRAIL test). Each program
combines strength, power, balance, walking, stretching
and cardiovascular exercises, in the named “VIVIF-
RAIL Wheel”. Training sessions are daily and weekly
organized (type of exercise, steps and reps) in
Table 1 Exclusion criteria for the HEAL study
- Acute heart attack (recent 3–6 months) or unstable angina
- Uncontrolled atrial or ventricular arrhythmias
- Aortic dissecting aneurysm
- Severe aortic stenosis
- Acute endocarditis / pericarditis
- Uncontrolled high blood pressure (> 180/100 mmHg)
- Acute thromboembolism
- Acute or severe heart failure
- Acute or severe respiratory failure
- Uncontrolled postural hypotension
- Uncontrolled acute decompensated diabetes mellitus
or low blood sugar
- A recent fracture in the last month.
- Coincident participation in any intervention trial
- HMB contraindication, intolerance, or allergy
- Have regularly performed exercise (> 20min > 3days/week)
in the last 3 months
- Malignant diseases (exceptions: basal or squamous-cell
skin carcinoma or carcinoma in situ of the uterine cervix)
- Revascularization within 1 year
- Severe loss of vision, hearing, or communicative ability
- Conditions preventing cooperation
Courel-Ibáñez and Pallarés BMC Geriatrics (2019) 19:188 Page 4 of 10
individual “Passports”. A summary of the exercise
program is shown in Fig. 2.
The VIVIFRAIL program has a free mobile app avail-
able on iOS and Android, the latest version of which,
(launched in January, 2019) allows the recording of the
results of the test to automatically assign each partici-
pant to a training program. The App includes a calendar
with a daily progression, training monitoring and rate of
perceiving effort assessment.
Functional capacity (primary outcome): The Short Phys-
ical Performance Battery (SPPB)  scores from 1 (low
mobility) and 12 (full mobility) points based on three
Table 2 Schedule of enrollment, interventions, and assessments
12th week post
25th week post
Eligibility screen ✓
Informed consent ✓
Randomized Allocation ✓
Functional capacity (primary outcome)
SPPB: Gait speed, balance, and 5-sit-to-stand ✓✓✓✓
Muscle strength and power
Grip strength ✓✓✓
1RM seated leg press ✓✓✓
1RM vertical bench press ✓✓✓
Sit-to-stand muscle power ✓✓✓
Frailty and fall risk
Frailty phenotype ✓✓✓
Falls history ✓✓✓✓
Fall risk assessment ✓✓✓✓
Body composition ✓✓
Blood pressure and resting heart rate ✓✓✓
Biochemical analyses ✓✓✓
Nutritional status ✓✓✓
Disability and comorbidity
Barthel index ✓✓✓
Lawton index ✓✓✓
Cognitive function ✓✓✓✓
Ex: 12-week of VIVIFRAIL multicomponent exercise program. HMB: dietary supplementation of HMB. Plac Placebo. SPPB Short Physical Performance Battery; 1RM
Courel-Ibáñez and Pallarés BMC Geriatrics (2019) 19:188 Page 5 of 10
tests: balance tests (tandem, semi-tandem and one foot
next to the other), gait speed and 5-sit-to-stand test.
The SPPB has been extensively administrated in older
adults [17,44]. The resulting scores are part of the
VIVIFRAIL test to determine each individual’sphys-
ical exercise program .
Maximal muscle strength and power output: grip
strength measurement (Jamar digital dynamometer,
NexGen ergonomics, Pointe Claire, Quebec, Canada)
, one repetition maximum (1RM) seated leg press
and vertical bench press strength (Salter Ltd., Barce-
lona, Spain) and muscle power (T-Force Dynamic
Fig. 2 Summary of the VIVIFRAIL multicomponent exercise intervention program. Individualization based on baseline testing scores. Full
Courel-Ibáñez and Pallarés BMC Geriatrics (2019) 19:188 Page 6 of 10
Measurement System, Ergotech Consulting SL,
Murcia, Spain) [46,47], sit-to-stand muscle power
, in the same order with a 3-min rest between
tests in order to diminish fatigue .
Frailty and fall risk: frailty phenotype determination
, complete falls history and fall risk assessment,
physical examination .
Body composition: Body composition will be assessed
using dual-energy x-ray absorptiometry - DXA (Hologic,
Bedford, MA; Discovery A), between 6:00 AM and 9:00
AM after a ≥10-h fast and after participants had voided
their bladders .
Blood pressure and resting heart rate: Systolic and dia-
stolic blood pressure, as well as resting heart rate will be
measured after 10 min of rest, two times 2 min apart
(M6 upper arm blood pressure monitor Omron. Omron
Health Care Europe B.V. Hoofddorp, The Netherlands).
Haematology: Erythrocyte count, haematocrit, haemo-
globin, platelets, leukocytes and erythrocyte mean cor-
puscular volume will be quantified by Coulter Cell
Biochemical analyses: glucose, high-density lipoprotein
(HDL), total cholesterol (TC), triglycerides (TG), glyco-
sylated haemoglobin (HbA
), thyroid-stimulating hormone
(TSH), C-reactive protein (CRP), albumin, prealbumine,
transferrin, insulin-like growth factors (IGF-1 and IGFBP-
3), creatine phosphokinase (CPK) and 25-hydroxyvitamin
D (25[OH]D). Blood analysis will be conducted with stand-
ard methods using an autoanalyzer. Insulin sensitivity will
be derived from the homeostatic model assessment for in-
sulin resistance (HOMA-IR).
Nutritional status: The Mini-Nutritional Assessment
(MNA-SF)  will be used to evaluate nutrition status
and malnutrition risk.
Sarcopenia: The SARC-F will be used to diagnose sar-
Disability and comorbidity: Barthel index  and
Lawton index  will be used to assess disability in
basic activities and instrumental activities of daily living,
respectively. Given the limitations of comorbidity in-
dexes in older people , we will consider comorbidity
when a participant presents two or more geriatric syn-
dromes from a list of selected geriatric syndromes, as
previously proposed .
Cognitive function and depression: the validated Spanish
version of the Mini-Mental State Examination (MMSE)
 will be used to assess cognitive function. Depression
will be assess with the Spanish version of the 15-item Yea-
savage geriatric depression scale .
Analysis will be performed on participants who
attended at least 80% the training sessions and
completed all the measurements. Treatment effects
will be tested using generalized linear models. All
models will be adjusted for the baseline outcome
value and repeated adjusting for gender, age, the
group effect, and confounding factors.
The trial was registered on ClinicalTrials.gov (identifier:
NCT03827499) on 01/02/2019.
This paper outlines the protocol for a randomized,
placebo-controlled study to determine the efficacy of
HMB supplementation in addition to 24-weeks of
multicomponent exercise and resistance training in
adults ≥70 years old. At the time of writing, the
study was ongoing (recruitment status). Baseline as-
sessment is planned to started in March 2019.
Maintaining old people’s health and protecting
them from frailty, muscle waist and cardiovascular
diseases will save billions in public care costs by
lengthening people’s healthy life, reducing the loss of
income due to premature death and reducing nursing
dependency . Evidence supports that multicompo-
nent exercise [8–10,17,61] and HMB supplementa-
tion [24–26] are effective in improving older adult’s
health and palliating functional metabolic diseases in
older people. However, thetrueeffectofHMBsup-
plementation combined with a tailored exercise pro-
gram is still unknown. Just a few trials have
investigated the combination of both [31–33], show-
ing promising results. Moreover, the implementation
of the new VIVIFRAIL multicomponent exercise pro-
gram for frail old people in addition to HMB supple-
mentation is still to be done.
The study results will be of high relevance to old
people living in nursing homes and their health care
providers. If the benefits of the combined VIVIFRAIL
and HMB are proven, this could be an alternative man-
agement strategy to consider in nursing homes with
older adults and people with functional metabolic dis-
eases and muscle-wasting conditions. In addition, the
current exercise intervention is inexpensive and freely
available (http://www.vivifrail.com/), which permits its
replication. The findings of the HEAL study will help
professionals from public health systems to identify cost-
effective and innovative actions to improve older peo-
ple’s health and quality of life, and endorse exercise
practice in older adults living in nursing homes.
1RM: One-repetition maximum; CRP: C-reactive protein; DXA: Dual-energy x-
ray absorptiometry; Ex-HMB: Exercise intervention with HMB; Ex-Plac: Exercise
intervention with placebo; HDL: High-density lipoprotein; HMB: β-hydroxy-β-
methylbutyrate; MMSE: Mini-Mental State Examination; NoEx-HMB: No
Courel-Ibáñez and Pallarés BMC Geriatrics (2019) 19:188 Page 7 of 10
exercise intervention with HMB; RCT: Randomized Control Trial;
SPIRIT: Standard Protocol Items: Recommendations for Interventional Trials;
SPPB: Short Physical Performance Battery; TC: Total cholesterol;
TG: Triglycerides; TSH: Thyroid-stimulating hormone
*The HEAL study group:
Jesús García Pallarés –Human Performance and Sports Science Laboratory,
Department of Physical Activity and Sport, Faculty of Sport Sciences,
University of Murcia, Spain.
Javier Courel Ibáñez –Human Performance and Sports Science Laboratory,
Department of Physical Activity and Sport, Faculty of Sport Sciences,
University of Murcia, Spain.
Ricardo Morán Navarro –Human Performance and Sports Science Laboratory,
Department of Physical Activity and Sport, Faculty of Sport Sciences,
University of Murcia, Spain.
Elena Saura Guillén –Endocrinology and Nutrition Service, University
Hospital Virgen de la Arrixaca, Murcia, Spain.
Alejandro Martínez Cava –Human Performance and Sports Science
Laboratory, Department of Physical Activity and Sport, Faculty of Sport
Sciences, University of Murcia, Spain.
Alejandro Sánchez Pay –Human Performance and Sports Science Laboratory,
Department of Physical Activity and Sport, Faculty of Sport Sciences,
University of Murcia, Spain.
Ángel Buendía Romero –Faculty of Sport Sciences, University of Murcia, Spain.
Silverio García Conesa –Faculty of Sport Sciences, University of Murcia, Spain.
JGP contributed in the conception of the idea for the study. JCI and JGP
contributed in the development of the protocol, organization and writing
the manuscript. All the authors read the draft, made contributions and
approved the final manuscript.
This protocol has been peer-reviewed and funded by the Autonomous Com-
munity of the Region of Murcia, Regional Program for the Promotion of Sci-
entific and Technical Research (Action Plan 2018), Seneca Foundation-
Agency of Science and Technology, Region of Murcia (ID: 20872/PI/18).
Availability of data and materials
Data are not available due to EU General Data Protection Regulation. Please,
contact the corresponding author if you are interested in study materials.
Ethics approval and consent to participate
This study was reviewed and approved by the Ethics Commission of the
University of Murcia, Spain (code: 2131/2018). All participants will sign an
informed consent according to the Declaration of Helsinki prior to data
Consent for publication
The authors declare that they have no competing interests.
Received: 9 February 2019 Accepted: 30 June 2019
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