Clinical Trial Details
— Status: Not yet recruiting
Administrative data
| NCT number |
NCT05860842 |
| Other study ID # |
2023-04 |
| Secondary ID |
|
| Status |
Not yet recruiting |
| Phase |
N/A
|
| First received |
|
| Last updated |
|
| Start date |
February 1, 2024 |
| Est. completion date |
September 30, 2025 |
Study information
| Verified date |
November 2023 |
| Source |
University of Roma La Sapienza |
| Contact |
Giuseppe Pugliese, MD, PhD |
| Phone |
+390633775440 |
| Email |
giuseppe.pugliese[@]uniroma1.it |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
Type 2 Diabetes (T2D) is a condition characterized by acelerated aging and is associated to
multiple comorbidities, and physical fragility and disabilitiy, all of which reduce life
expectancy and quality of life. Physical exercise has been demonstrated to have metabolic and
cardiovascular benefits in T2D. Also, lack of exercise and sedentary behavior are major
predictors of cardiovascular morbidity and mortality and all-cause mortality. Some evidence
suggests that individuals with T2D have a reduced exercise capacity and exercise tollerance
compared to non-diabetic individuals.The reasons behind such difference are not thoroughly
explored, but may be connected to acute and chronic effects of hyperglycemia. Reduced
trainability might be a marker of early aging and physical disalbility. This study aims to
define respiratory, cardiovascular, neuromuscular, inflammatory, hormonal and metabolic
determinants of trainability in persons with T2D. Results will help to answer the question
whether it is the low trainability that reduces exercise capacity or it is the low exercise
participation that determines a low exercise capacity.
Description:
Type 2 diabetes (T2D) is an age-related disease that is considered a condition of accelerated
aging. It is in fact associated with multimorbidity, frailty and physically disability in
older adults substantially impairing quality of life as well as with a reduced lifespan due
to the occurrence of acute and, particularly, chronic complications, the most important of
which is cardiovascular disease (CVD).
Reduced exercise capacity as a predictor of adverse outcomes in aging and age-related
diseases. Physical inactivity and sedentary behavior have shown to be associated with
increased all-cause and CVD morbidity and mortality in the general population and in people
with diabetes. Both cardiorespiratory and muscle fitness have been shown to be independent
predictors of death and to compensate for increased fatness, at least in part. In particular,
exercise capacity or tolerance, i.e., the maximum amount of physical exertion that an
individual can sustain, has been shown to predict mortality beyond traditional CVD risk
factors and proposed as prognostic variable to be included in predictive algorithms in
asymptomatic aging individuals or in those suffering from chronic disorders such as T2D. It
can be assessed by cardiopulmonary exercise testing and usually measured as peak power output
(PPO or peak work) or peak oxygen consumption (VO2peak). Though also dependent on the
individual genetic background, the level of physical fitness/exercise capacity is largely
determined by the amount of physical activity (PA), which is therefore strongly recommended
in the general population and in people with T2D, together with reduction (and break) of
sedentary time, which exerts detrimental effects independent of PA. In patients with T2D, in
addition to providing overall health benefits, PA/exercise is effective in improving glucose
control, CVD risk factors, and well-being, as also shown by our group.
Several studies have shown that patients with T2D have a reduced exercise capacity or
tolerance as compared with non-diabetic individuals, though other reports failed to show any
defect, especially if blood glucose is well-controlled. Studies investigating the mechanisms
underlying the impaired exercise (aerobic) capacity have reported abnormalities in the
ability of (a) lung to oxygenate arterial blood; (b) heart and vascular system to meet the
circulatory demands; and (c) peripheral tissues to extract oxygen. In particular, decreased
ventilatory efficiency, reduced peripheral oxygen extraction, impaired heart rate adjustment,
and lower anaerobic threshold, have been shown in T2D individuals compared to non-diabetic
subjects. In addition, T2D patients showed neuromuscular impairment with increased muscular
fatigability. Our group has contributed to characterize the neuromuscular dysfunction of T2D
by showing a reduction of isometric and dynamic muscle strength and endurance.
The reasons for the lower exercise capacity in the aging T2D population are unclear.
However, due to the cross-sectional design of most of the existing studies, the reasons for
the lower exercise capacity in T2D patients are still unclear. On the one hand, these
individuals might exercise less than non-diabetic individuals, as shown by several reports,
consistent with the known role of physical inactivity and sedentary behavior as risk factors
for the development of the disease. On the other hand, people with T2D might respond less to
exercise training (reduced trainability), due to effects of hyperglycemia. These effects
include the acute impact of poor glycemic control, with several deficits at least partially
reversible upon improvement of HbA1c levels, and the chronic consequences of hyperglycemia,
with subtle impairments in ventilatory, cardiorespiratory and neuromuscular function
occurring prior to the onset of overt complications, the relation of which with reduced
exercise capacity is well-established. In addition, a reduction in VO2 peak has been observed
in first-degree relatives of T2D individuals versus accurately matched controls suggesting a
possible role of the genetic background predisposing to T2D. Another mechanism which might be
involved in the reduced exercise capacity and trainability is the chronic low-grade
inflammation characterizing patients with T2D and the metabolic syndrome and potentially
counteracted by engaging these individuals in exercise training programs, as shown by our
group.
Impaired exercise capacity and reduced trainability can be considered early markers of aging,
cardiometabolic disorders and physical disability. Assessing exercise capacity and its
cardiorespiratory and neuromuscular determinants may therefore predict adverse outcomes, aid
in designing and implementing personalized training interventions, and serve as a tool for
evaluating the effect of therapeutic strategies in aging people and/or individuals with T2D.
2. AIMS
This project is aimed at assessing trainability of patients with T2D in order to clarify:
a. whether reduced exercise capacity is due to an impaired response (trainability) or a
reduced adherence to training; b. which are the mechanisms involved and the respiratory,
cardiovascular, neuromuscular, inflammatory, hormonal, and metabolic parameters predicting
trainability.
3. DESIGN AND METHODS
3.1 Design This is a single-center, open-label, longitudinal intervention study comparing T2D
versus non-diabetic individuals entitled "EXercise capacity and TRAinability in Type 2
Diabetes (EXTRA-T2D)".
Participants will be engaged in:
1. a 6-month supervised aerobic and strength training program, to assess response (and
impact of glycemic control);
2. a 6-month post-training follow-up, to assess adherence (and possible impact of
detraining).
Measurements will be performed at baseline (T0), at the end of the 6-month training (T1), and
at the end of the 6-month post-training follow-up (T2).
At enrollment, participants will be given an accelerometer and an activity diary to monitor
activities of daily life throughout the entire 12-months period. At each of these time
points, participants will be given the questionnaires for the assessment of PA, barriers to
exercise, health-related quality of life (QoL), and psychological well-being. They will be
then evaluated for the study endpoints on four different days, on days 1-3 at the Exercise
Physiology Laboratory of the University of Rome "Foro Italico" and on day 4 at Sant'Andrea
University Hospital (University of Rome "La Sapienza").
On day 1, the accelerometer and questionnaires will be collected and participants will
undergo assessment of anthropometric parameters and ventilatory and cardiorespiratory
function at rest, followed by a ramp incremental cycling test until task failure in order to
assess endurance exercise capacity as peak power output (PPO) and ventilatory and
cardiorespiratory function in response to exercise.
On day 2, the ramp test will be repeated, as previously suggested, in order to partition
within-participant day-to-day variability from the assessment of trainability.
On day 3, participants will perform neuromuscular tests. On day 4, participants will undergo
routine biochemical testing and blood sample collection as well as cardiac and muscle
magnetic resonance imaging (MRI) (at T0 and T1 only).
3.1.1. Participants This study will enroll 24 patients with T2D, 12 females and 12 males, and
24 age-and sex-matched non-diabetic volunteers serving as control group.
Absence of complications will be assessed based on normal ECG, carotid and lower limb Doppler
ultrasound, fundus oculi, albuminuria, eGFR, vibration perception threshold as measured by a
biothesiometer. Additional criteria for non-diabetic participants are absence of CVD and
renal disease, as assessed based on normal ECG, carotid and lower limb Doppler ultrasound,
albuminuria, and eGFR.
3.1.2. Recruitment Patients with T2D will be recruited at the outpatient Diabetes Clinic of
Sant'Andrea University Hospital (University of Rome "La Sapienza"). Patients fulfilling the
above criteria will be identified by the Diabetologist, asked to sign a statement of informed
consent, and subjected to a cardiologic examination for cardiovascular evaluation, including
a resting ECG and, based on clinical judgment, an echocardiogram and/or an ECG treadmill
test, to obtain clearance for participation in the trial.
The non-diabetic volunteers will be recruited among non-diabetic patients attending the
Endocrinology Unit of Sant'Andrea University Hospital and the University personnel at both
the Sant'Andrea University Hospital (University of Rome "La Sapienza") and the University of
Rome "Foro Italico".
3.1.3. Intervention Both T2D patients and non-diabetic controls will perform a 6-month
supervised exercise training program at the gym facility of the Center for Sports and
Physical Exercise Medicine of the Foundation of the University of Rome "Foro Italico",
equipped with high-tech, new-concept machines donated by Technogym (Cesena, Italy) to the
University of Rome "Foro Italico" as a result of joint application of the two units involved
in this project to a call of the Italian Diabetes Society.
The program will consist of 2 sessions/wk of 75 min each, consisting of 5-min warm-up, 30-min
endurance exercise, 30-min resistance exercise, 5-min flexibility and 5-min cool-down. The
training load will be monitored with the CR-10 Rating of Perceived Exertion (RPE) scale and
the NASA task load index scale during each training session.
The 30-min endurance exercise bout will be performed on a cycle ergometer (Excite Live Run,
Technogym S.p.A.) recording power output, while also measuring respiratory frequency (fR) and
HR with a wearable device (Howdy Senior, ComfTech, Monza, Italy) and RPE. The work rate will
be initially set at 50% of the PPO at the incremental test aiming for an RPE of 5/10 at the
end of the bout, hence allowing for within session adjustments in power output to reach this
target. A submaximal incremental test will also be performed every month to adjust exercise
intensity progression and assess changes in fR, HR or RPE. The starting power output will be
set at 30 W and increased by 10W every min until reaching the 85% of the HR peak achieved in
the experimental test.
The 30-min resistance exercise bout will consist of 8 to 10 exercises involving large muscle
groups including the use of electronically controlled resistance training machine
(Biostrength, Technogym), equipped with sensors allowing for real-time guidance of movement
execution, measurement of maximal dynamic force (1-Repetition maximum, 1RM), and
post-training extraction of raw mechanical data. At the beginning of the training program,
participants will perform 3 sets of 12 repetitions at 60% of 1RM using the leg press, chest
press and low row Biostrength line machines. The 1RM test on the three machines will be
repeated every 2 wks to change the 60% target accordingly.
In diabetic participants, glycemic variations will be monitored before, during and after each
training session, by means of a glucose meter, to decide whether patients are ready to
perform the exercise session or need carbohydrate integration or treatment adjustment, to
avoid adverse events during the session and the following 6-48 hours (e.g., hypoglycemic
events).
3.1.4. Outcome measures The primary endpoint is change in endurance exercise capacity, i.e.,
PPO. Secondary endpoints include changes in ventilatory, cardiorespiratory and neuromuscular,
and inflammatory parameters. Anthropometric, metabolic and (in males only) hormonal
parameters, adherence and barriers to exercise, health-related QoL, and psychological
well-being will be also assessed.
These outcomes will be assessed in the whole cohort, to evaluate overall trainability, in
females versus males separately, to assess sex differences, and in each individual, to
identify patients at risk.
3.2. Measurements 3.2.1. Primary endpoint Exercise capacity will be measured as the PPO
achieved at the end of the ramp incremental test, registered to the nearest second. The test
will be performed at the Exercise Physiology Laboratory of the University of Rome "Foro
Italico" on an electromagnetically braked cycle ergometer (Lode Excalibur Sport, Groningen,
the Netherlands). After 2 min of baseline pedaling at 20 W, the power output will be
increased by 1 W/s (20 W/min) until task failure (i.e., the inability to maintain pedaling
cadence at 70 rpm for more than 10 s). Participants will be asked to maintain this cadence
throughout any ramp test to eliminate the potentially confounding effect of cadence on
responses measured with a metabolic cart (Quark PFT, Cosmed, Rome, Italy). Trainability will
be measured for single participants as the percentage difference from the average PPO of the
incremental tests at T1 and the average PPO of the two incremental tests at T0 (ΔPPO). The
ΔPPO of both T2D and control groups will then be calculated and compared by averaging ΔPPO of
single participants in each group.
3.2.2. Secondary endpoints Ventilatory function
The following parameters will be measured at the end of the ramp incremental test performed
at the Exercise Physiology Laboratory of the University of Rome "Foro Italico":
1. Respiratory frequency (fR);
2. Perceived exertion and dyspnea, assessed every min during the rampThe incremental test
along with ventilatory variables;
3. Ventilatory efficiency, measured as the minute ventilation (V̇E) to carbon dioxide
output slope obtained during incremental exercise;
4. Resting pulmonary diffusion capacity for carbon monoxide (DLCO) and related
subcomponents (i.e., pulmonary capillary volume and alveolar capillary membrane
diffusing capacity);
5. Forced vital capacity and pulmonary function (maximum ventilatory ventilation, pulmonary
volumes, maximal inspiratory pressure and maximal expiratory);
6. Ventilatory flow morphology. Cardiorespiratory function
The following parameters will be measured at the end of the ramp incremental test performed
at the Exercise Physiology Laboratory of the University of Rome "Foro Italico":
1. V̇O2peak;
2. Ventilatory thresholds (first and second);
3. Metabolic efficiency, as V̇O2-work rate slope;
4. HR and HR recovery (HRR), computed by subtracting the HR value at 1 min after test end
from the HR peak during the test;
5. Oxygen pulse, as V̇O2/HR ratio;
6. Blood pressure, measured before, during and after incremental test with an automatic
machine integrated with the metabolic cart;
7. HR variability (HRV), as an index of sympathetic and parasympathetic function.
Neuromuscular function Participants will perform different neuromuscular tests at the
Exercise Physiology Laboratory of the University of Rome "Foro Italico" to
comprehensively evaluate the neuromuscular function of the knee extensors, while
measuring force and HDsEMG activity of vastus lateralis (VL) and vastus medialis (VM) of
the dominant limb. Tests of maximal isometric force, sustained contractions, trapezoidal
changes in force and muscle endurance will be performed.
The following features will be extracted:
1. Muscle strength and endurance;
2. Neural drive;
3. Sources of neural drive;
4. Motor unit conduction velocity (MUCV);
5. Muscle fibre conduction velocity (MFCV);
6. Neuromuscular efficiency;
7. Neuromuscular manifestations of fatigue;
8. MU recruitment and derecruitment strategies;
9. Force steadiness. Cardiac and muscle MRI Cardiac and muscle MRI will be performed at the
Radiology Unit of Sant'Andrea University Hospital (University of Rome "La Sapienza") in
all participants at T0 and T1 only using a GE Signa 1.5 Tesla (GE Healthcare, Milan,
Italy).
At cardiac MRI, left ventricular (LV) and right ventricular (RV) images will be obtained to
obtain measures of:
1. LV and RV mass;
2. end-diastolic and end-systolic volumes;
3. stroke volumes;
4. ejection fraction;
5. cardiac output.
At thigh MRI, the following parameters wil be assessed:
1. muscle cross-sectional area;
2. intramuscular fat;
3. muscle density. Inflammatory profiling The following cytokines will be assayed in
duplicate at the Department of Translational and Precision Medicine of the University of
Rome "La Sapienza" by multiplex biometric ELISA-based immunoassay, using custom assay
(Bioplex, Bio-Rad Lab) at T0, T1 and T2: Interleukin (IL)-1β, IL-2, IL-4, IL-6, IL-8,
IL-12p70, interferon (IFN)-γ, and tumor necrosis factor (TNF)-α. Serum samples will be
analyzed in the laboratory of the Principal Investigator.
Steroidomics Since aging and T2DM are associated with male hypogonadism and alteration of the
hypothalamus-pituitary-adrenal axis, gonadal and adrenal steroids will be assayed in blood
and salivary samples from male participants at T0, T1 and T2 at the Department of
Experimental Medicine of the University of Rome "La Sapienza" using a recently validated
in-house methodology capable of assessing up to 18 steroids simultaneously. Blood and
salivary samples will be sent to Prof. Gianfrilli, Department of Experimental Medicine,
Sapienza University of Rome, will be responsible for these analyses.
Metabolic parameters: Fasting glucose, insulin, triglycerides, total, HDL, and LDL
cholesterol, and (in T2D patients only) HbA1c will be assessed at Laboratory Unit of
Sant'Andrea University Hospital (University of Rome "La Sapienza") in all participants T0, T1
and T2.
Anthropometric parameters: Anthropometric characteristics (body weight and height with
calculation of BMI, waist and hip circumference with calculation of waist-to-hip ratio,
waist-to-height ratio, and A Body Shape Index [ABSI]) and body composition (by bioimpedance
analysis) will be evaluated in all participants.
Exercise adherence and barriers: During the 12 months experimental period, each participant
will be given a wrist-worn triaxial accelerometer (GENEActiv, Activinsights, Cambridgeshire,
UK) and will also be requested to register daily activities by filling activity diaries. In
addition, participants will be asked to complete the Italian version of the short form
International Physical Activity Questionnaire. Perceived barriers to exercise will be also
evaluated by using the Self-perceived Barriers for Physical Activity Questionnaire.
Participants will be evaluated for health-related QoL and psychological well-being by the
Italian version of the SF-36 Health Survey and the WHO-5 questionnaire, respectively.
3.3 STATISTICAL ANALYSIS
An a priori power analysis has been conducted for sample size estimation, using the G*power
3.1.9.2 Software. Given the paucity of studies reporting differences in trainability between
T2D and healthy individuals, we have been cautious not to overestimate the effect size of any
potential difference in PPO. Hence, a small effect size (i.e., 0.25) has been considered for
the calculation, along with the following input information:
- Statistical test: ANOVA repeated measures, within-between interaction;
- α value: 0.05;
- 1-β: 0.8;
- Groups: 2;
- Measurements: 2;
- Correlation among repeated measures: 0.7. The resulting estimated sample size was 22
participants per group but, considering a dropping out of 10%, 24 participants per group
will be recruited.
To assess differences in exercise capacity between T2D patients and non-diabetic controls,
baseline (T0) values of the primary endpoint (PPO) and secondary endpoints (ventilatory,
cardiorespiratory, and neuromuscular parameters) will be compared.
To assess differences in trainability between T2D patients and non-diabetic controls, change
from baseline (T1-T0) in the primary endpoint and secondary endpoints will be compared.
To assess differences in adherence between T2D patients and non-diabetic controls, change
from end-of-training (T2-T1) in the primary endpoint and secondary endpoints will be
compared.
The unpaired Student's t test or the Mann-Whitney U test will be used for parametric and
non-parametric variables, respectively.
In addition, univariate correlations by Spearman's rho and multivariable linear regression
analyses will be used to identify correlates of change from baseline in exercise capacity
(i.e., trainability).
