Clinical Trial Details
— Status: Completed
Administrative data
| NCT number |
NCT04957589 |
| Other study ID # |
19026_CMMP |
| Secondary ID |
255016 |
| Status |
Completed |
| Phase |
N/A
|
| First received |
|
| Last updated |
|
| Start date |
January 1, 2020 |
| Est. completion date |
December 1, 2022 |
Study information
| Verified date |
July 2022 |
| Source |
University of Nottingham |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
Sarcopenia is defined as the incremental age-related loss of skeletal muscle in humans which
generally begins from forty years old. It is associated with an overall reduction in quality
of life and increased morbidity and mortality. Patients with type two diabetes mellitus
(T2DM) are particularly at risk of developing sarcopenia, partly due to the condition and
also due to the common incidence after or during middle age. A promising
recently-investigated and effective conservative approach to T2DM is through very low calorie
diets (VLCD). Some studies have shown that the diabetic status of some patients can be
reversed through VLCD. However, VLCD will theoretically result in an acceleration of
sarcopenia. This presents as a limiting factor for the implementation of VLCD in this at-risk
patient group. Skeletal muscle tissue is encouraged to grow in size or be maintained through
two means - an increase in circulating protein breakdown products, or through resistance
exercise (RE). Additionally, RE has been shown to increase the body's sensitivity to insulin,
the main hormone which controls circulating glucose levels and is frequently impaired in
T2DM, as well as temporarily decreasing glucose levels. The precise mechanism by which these
happen is not fully understood yet. In this study, the effect of a VLCD is used, alongside
one form of exercise (high intensity interval training, HIT), in overweight, middle-aged male
patients with T2DM. 10 patients are to be recruited into each group (control/VLCD-only and
VLCD with HIT) at our centre. Patient weight, markers of muscle protein synthesis, glucose
levels and changes to blood vessels will be investigated before, during and after across a
six week timeframe. Investigations will include muscle and fat biopsies, blood samples,
ultrasound scans, strength testing and deuterium oxide (D2O) isotope ingestion for later
non-invasive body fluid sample mass spectrometric analysis.
Description:
Very low calorie diet (VLCD) is increasingly being utilized to improve cardio-metabolic
outcomes in overweight/obese individuals with type 2 diabetes mellitus (T2DM), but concerns
regarding its association with skeletal muscle mass losses persist, especially in
middle-aged/older individuals, who are already at risk of accelerated sarcopenia. This is
particularly relevant in people at risk of developing diabetes due to the rising incidence
and prevalence of diabetes among older patients as well as accelerated sarcopenia in diabetes
compared with non-diabetes. Given that low skeletal muscle mass and function is linked to
mortality, frailty, and adverse cardio-metabolic outcomes, increased understanding of the
mechanisms of VLCD-induced muscle atrophy, and novel strategies to overcome this is crucial
to optimize healthy ageing. Alongside nutrition, physical activity is another key driver of
muscle protein synthesis, with habitual physical activity required to maintain muscle mass. A
number of studies have shown that even short-term muscle disuse (or reduced use in the form
of reduced ambulation (e.g. 2 weeks of <1500 steps/day) or limb immobilization causes muscle
wasting. Exercise has also been shown to improve metabolic control by increasing muscle
glucose uptake during muscle contractions via insulin-independent mechanisms, and also by
increasing skeletal muscle insulin sensitivity following physical activity. HIT has been
shown in a number of studies to improve both cardiovascular and metabolic function in a
variety of cohorts. Therefore, this study aims to quantitatively determine whether HIT helps
prevent a major physiological detrimental effect of VLCD.
This study will randomise volunteers to:
1. VLCD ("Lighter Life" meal replacement product, total 600 calories (kcal)) alone (200kcal
free allowance) (N=10)
2. VLCD and HIT (200kcal free allowance) (N=10) This will be undertaken in overweight and
obese patients (BMI=27-50kg/m2) of male gender and between the ages of 35-65 years.
Based on a power calculation derived from recently-published trial data utilising VLCDs
and with MPS as the primary outcome, a minimum of 8 participants per group would be
sufficient, with a further N=2 per arm (an increase in 25%) implemented to account for
drop-outs.
The study will aim to recruit (to allow for potential non-completion) 10 subjects per group.
Volunteers would undergo detailed physiological and metabolic investigations before and after
interventions
1. Skeletal muscle mass, function and protein metabolism
2. Vascular function (microvascular perfusion, macrovascular blood flow and endothelial
function)
3. Cardio-metabolic status (glucose handling, cardiorespiratory function, central blood
flow parameters)
4. mechanisms regulating changes in glucose handling and muscle protein turnover It is
anticipated that HIT may ameliorate VLCD-induced reductions in skeletal muscle mass and
function, by boosting the molecular signals which involve the retention of muscle mass.
This adjuvant exercise interventions may also elicit improvements in cardio-metabolic
health (vs. VLCD alone) via improvements in blood vessel function.
The findings from this project could enhance our understanding on the role of VLCD in
inducing improvement in cardio-metabolic health, provide rapid, practical low cost clinical
interventions for people with T2DM and/or obesity, while unearthing potential new therapeutic
targets for the future management of high blood sugar and obesity in people with T2DM.
STUDY PROTOCOL After having passed screening and being formally enrolled, participants will
be randomised and stratified (described previously), and then attend the department twice
prior to their intervention commencement, with each day consisting of a full study day,
whereby the various primary and secondary outcome measurements will be performed.
On the first study day (D-5 from intervention), subjects will be asked to fast from midnight
(except for water). This first 'study day' will consist of, in chronological order, repeat
height and weight measurement, a baseline urine sample, DXA and oral glucose tolerance test
(OGTT) with concurrent questionnaire completion, followed by lunch. This is followed by hand
grip dynamometry, electromyogram, maximal voluntary isometric contraction (MVC), the Short
Physical Performance Battery (SPPB), and 1 repetition-maximum (1RM) testing of three lower
body (leg press, hamstring curl, quadriceps extension) and three upper body movements (chest
press, machine row, machine pulldown). Thereafter, participants would be fitted with an
Actiheart monitor, followed by a staggered dosing of a D2O bolus with a concurrent bolus dose
of D3-creatine. Additionally, they would be provided with several collection vessels (24 hour
jar, two collection pots for 48 hour and 72 hour spot samples for the D3-creatine; a saliva
collection pot to be filled two hours following the D2O bolus). They would also be provided
with a loading dose of 3-methylhistidine (3MH) to be taken one day prior to the second study
day (D-1 from intervention). Finally, they would be provided with an updated itinerary of the
available VLCD meals for selection.
Between the two study days (D-4 to D-1 from intervention), the participant would collect
their D3-creatine-containing urine at home (24 hour period, and 48 & 72 hour spot samples).
Additionally, one day prior to the second study day (D-1 from intervention), participants
would be asked to consume the 3MH bolus at precisely 13:00. During the interim period, the
participant would also be contacted to receive their preferences for meal profiles, which
would be organised by the department. Finally, if the participant had been randomised into
the 'VLCD only' group, they will advise the research team of their preferred food items
(vegetables and/or nuts) during this interval, in order for a calculation of the approximate
breakdown of calories that may be required to achieve a 200kcal value.
On the second study day (D0 from intervention), subjects would once again be asked to fast
from midnight (except for water). Upon attendance, they would be asked to provide a fasting
saliva sample, blood (a repeat of the screening panel, alongside the '0 hour' serum 3MH level
and D2O baseline measurement). Additionally, they would have their estimated 50% 1RM
calculated for the quadriceps leg extension of their dominant leg (for utilisation in the
subsequent analyses that day). They will also be expected to return their Actiheart monitor
and D3-creatine samples for subsequent analysis.
Thereafter, the participants would undergo (in chronological order) abdominal adipose tissue
biopsy, vastus lateralis muscle biopsy (non-dominant leg), vastus lateralis ultrasound
assessment (dominant leg), contrast-enhanced ultrasound scan (using the Sonovue agent;
dominant leg), leg blood flow (dominant leg), flow-mediated dilation (dominant arm), and
cardiopulmonary exercise testing (CPET). Throughout, across a four hour period from 09:00 to
13:00, serial measurement of the participant's serum 3MH levels are performed. At the end of
the session, the participant would be provided with two to three weeks of VLCD meals (per
their previously-agreed profile choices pending availability), alongside a diet and sleep
diary. Further, they will be provided with the details of a registered dietician for support,
and six once-weekly 'top up' doses of D2O, with the adjoining saliva sample vessels, to be
filled immediately prior to 'top up' and two hours afterwards.
The day after, the participant will commence their VLCD diet (D1), and will be expected to
attend the department for a brief period several days afterwards (D4-5) for an inspection of
their biopsy incision sites by a research clinician.
Within weeks three to four of the intervention, a peri-intervention study day will be
undertaken, whereby the participant would have repeat serial 3MH testing (as described in the
second pre-intervention study day), alongside another set of repeat blood tests (as described
in the first pre-intervention study day). All D2O saliva samples generated up to this
juncture may be submitted to us at this time. The participant would also be refitted with an
Actiheart monitor, to be worn for five full days.
Following the completion of six full weeks of interventionIn the sixth and final week of
their intervention period, the participants would be brought in for the post-intervention
study days, which fully replicate the procedures described in the pre-intervention study
days, with the exception of a D2O loading dose, and the returning of the Actiheart monitor
worn following the peri-intervention study day. Thus, these final two post-intervention study
days would occur on week six day two and week six day seven of the intervention period.
After the post-intervention study days have been completed, the participant would once again
attend the department after several days for a biopsy site incision inspection, in addition
to the organisation of their reimbursement and guidance with respect to transitioning towards
an increased calorie intake post-intervention All subjects will have 6-week intervention
period of VLCD nutritional intervention with LighterLife VLCD meal replacement diets,
600kcal/day with 100% recommended daily allowance (RDA) vitamins and minerals. Meal
replacements, which will be acquired from LighterLife, comprise of four food packs a day in
the forms of soups, porridge, bars and drink mixes.
