Clinical trial NCT03019796
Conditions: Exercise Therapy Metabolic Syndrome X Cardiorespiratory Fitness
Sponsor: University of Castilla-La Mancha
Start date: 2015-07-01; Completion date: 2020-08-01
Enrollment: 40 participants; Allocation: RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
To analyze the effects of different exercise training modalities (continuous, intervallic, and resistance training) on cardiorespiratory and metabolic fitness of metabolic syndrome patients when this training interacts with their habitual medication.

Detailed description:
Objective: The purpose is to study in a group of adults with metabolic syndrome and obesity, the effects of different modalities of exercise training on cardiorespiratory and metabolic fitness. The main objective is to weight the effects of exercise training separately and in conjunction with the subject's habitual pharmacological treatment to identify the best combination of drug and exercise.

Methods and design: Randomized, pretest-posttest control group experimental design. Project developed in a single center with the collaboration of the regional public health system.

Subjects: Will be referred by their primary care physicians to our study unit. Up to 40 subjects all of them with metabolic syndrome will be recruited (at least 20% women).

Measurements:

1. Specifically, the investigators, will study cardiovascular adaptations that increase, i) maximal aerobic capacity measured by VO2max, ii) anaerobic and respiratory compensation point ventilatory thresholds, iii) arterial stiffness, measured by pulse wave velocity (SphygmoCor System), v) central and peripheral blood pressure, and iv) biological markers of endothelial dysfunction using reactive hyperemia with a laser Doppler fluxmeter in central and peripheral blood vessels.
2. The metabolic adaptations under study will include, i) insulin sensitivity by HOMA-IR, ii) fat oxidation by indirect calorimetry

Arms: arm 1: Subjects first receive the PLACEBO tablet during 72 hours (full withdrawal). After a week of taking again their medication (MEDICATION TRIAL), they will be tested again. This procedure will be repeated before and after 4 months of aerobic training. arm 2: Subjects first receive their antihypertensive MEDICATION tablet (habitual dose prescribed by their primary care doctors). After a week they will take a PLACEBO tablet for 72 hours and will be tested again. This procedure will be repeated before and after 4 months of aerobic training.
Interventions: intervention 1: MEDICATION AND EXERCISE TRAINING
Intervention descriptions: intervention 1: PARTICIPANTS WILL BE (IN A RANDOMIZED BLINDED FASHION) WITHDRAWN OF THEIR HYPERTENSIVE MEDICATION (I.E., PLACEBO) IN ONE OCCASION AND TESTED WITH THEIR MEDICATION IN ANOTHER, WITH A WEEK WASHOUT PERIOD.

THIS TESTING WILL BE REPEATED AFER 4 MONTHS OF EXERCISE TRAINING (48 SESSIONS OF 43 MIN EACH ONE).

Protocol documents:
ICF_002.pdf: 
1 
STUDY TITLE 
INTERACTIONS BETWEEN PHYSICAL TRAINING AND 
MEDICATION IN PATIENTS WITH METABOLIC SYNDROME 
INFORMED CONSENT FORM (30 AUGUST, 2017) 


2 
INFORMATION SHEET AND INFORMED CONSENT FOR THE PARTICIPANT 
(adapted to August 30, 2017) 
Study title. INTERACTIONS BETWEEN PHYSICAL TRAINING AND 
MEDICATION IN PATIENTS WITH METABOLIC SYNDROME 
Research team: 
• Ricardo Mora Rodríguez (Responsible for the project). University Professor,
Exercise Physiologist; Faculty of Sports Sciences. University of Castilla-La
Mancha (UCLM)
• Juan Fernando Ortega Fonseca. Graduate in medicine and surgery. Specialty in
Sports Medicine. Doctor from the University of Castilla-La Mancha (UCLM).
• Félix Morales Palomo. Master in Exercise Sciences. Doctoral student at the
University of Castilla-La Mancha.
• Miguel Ramírez Jimenez. Master in Exercise Sciences. Doctoral student at the
University of Castilla-La Mancha.
Objective. Being overweight leads to abdominal obesity and this, over time, to 
hypertension, dyslipidemia and diabetes. To prevent this development, their doctor 
prescribes medication. The objective of this study is to determine if physical 
training amplifies the actions of the medications that you have been prescribed. 
Requirements to participate. You and 40 other adults between the ages of 25 
and 65 will participate in this study. All will be overweight and will not regularly 
participate in sports activities. In addition to being overweight and abdominally 
obese, you must have 2 other metabolic syndrome factors (hypertension, high 
fasting glucose or triglycerides, or low levels of “good” cholesterol). You are 
advised to seek a physician's opinion before enrolling in this study. You must not 
have any other endocrine pathology other than the one that resulted in the 
prescription of your medication. If you are a woman, you must not be pregnant or 
seek pregnancy in the next 4 months to participate in this study. 
Other exclusion criteria will be: recent surgery, cardiovascular disease 
(especially coronary disease, heart valve disease, heart failure, complex 
ventricular arrhythmias), kidney, liver, endocrine (other than pre-diabetes), 
respiratory or neuromuscular diseases. 
Preliminary / final tests. Before starting the study, a medical history with 
exploration will be taken, and you will be asked to undergo a sub-maximal and a 
MAXIMUM stress test, pedaling on a cycle ergometer. At rest and during exercise 
we measure the response of your heart using an electrocardiograph (in case you 
have not had this measurement from you in the last 12 months) to rule out 
abnormalities of the heart or other components of the cardiovascular system. In 
addition, during the test part of the air you exhale will be collected to calculate your 


3 
oxygen consumption and your maximum aerobic capacity. All these procedures 
will be performed by the sports medicine doctor of the research team. 
Analytics. On the day of the preliminary / final test, you will be given a flyer to go 
to a clinical laboratory on an empty stomach for an extraction (approximately 10 cc 
of venous blood). You must allow at least 24 hours between the preliminary / final 
maximal effort test and the analytical one. 
Physical Training: You will undertake to attend training sessions for 3-4 months 
at the university facilities on the Arms Factory campus. The exercise will be 
performed under the supervision of a sports science graduate and will be 
performed on an exercise bike. The training program will consist of 3 weekly 
sessions for 4 months of intense aerobic exercise. The workload will increase as 
training adaptations occur. At each exercise session, your heart rate will be 
measured. Your maximum heart rate and weight will be measured every 2 weeks. 
Experiment Tests: Depending on the type of medicine you take, you will be asked 
to go to the laboratory in the morning (7-9 am), without having had breakfast or 
having trained during the previous 2 days on 4 occasions. These tests are different 
in that you will be in each of the following situations: 
a) CONTROL. Participants refrain from exercising 48 hours before the test and 
from taking their medication 72 hours before the test.
b) TRAINED. Participants abstain from taking their medication 72 hours before the 
test and do an exercise session in the lab.
c) MEDICATION. Participants refrain from exercise 48 hours before the test but 
take their usual dose of medication.
d) TRAINED + MEDICATION. Participants take their usual medication before the 
test and do an exercise session in the laboratory.
Measurements in each test. 
Estimation of body composition. It will be weighed naked and carved. Next, the 
waist circumference will be measured. The amount of body fat will also be 
calculated with a device that circulates through your body a weak electrical current 
that you will not feel (electrical bioimpedance). 
Rest measurements. After these measurements, you will lie on a table, an elastic 
band will be placed around your chest to measure your heart rate, and a pressure 
cuff. Next, on the other arm, we will place a cuff that will be inflated to measure 
your systolic and diastolic pressure 3 times. Depending on the medication you 
take, (antihypertensive, hypoglycemic, statins) you will be given one of the 
following techniques. Measurement of your resting metabolism, by analyzing the 
exhaled air for 30 minutes. A non-invasive measurement of the speed of blood flow 
in your body called cardiac output. The ability of the cutaneous veins in the skin of 
your forearm to dilate and their production of nitric oxide in the blood. Auscultation 
of the femoral artery in the groin and the carotid artery in the neck to measure the 
shape and velocity of pressure waves at these locations. 
Intravenous glucose tolerance test, infusion of glucose tracers to calculate your 
body's rate of glucose production. Placement of a transterminal sensor that will 


4 
measure glucose concentration on an outpatient basis. 
Placement of a pressure cuff to measure blood pressure for 24 hours on an 
outpatient basis. 
Measurements during exercise. Depending on what medication you take 
(antihypertensive, hypoglycemic, statins) some of the measurements described will 
be performed during rest. 
Risks and discomforts. There is a risk of developing a small hematoma (effusion) 
where the blood is drawn on the arm. This risk is reduced by applying pressure for 
10 minutes after removing the needle. There is a risk of infection, which is 
minimized with the sterile procedures that we follow and general care of the 
puncture that will be indicated. Some people get dizzy during arm skin punctures, 
but the risk of an accident due to dizziness is reduced by performing the puncture 
with you lying on the table. During the 3 minutes of occlusion of the flow to the 
forearm, you may feel your fingers tingle. This occlusion time is not long enough to 
create problems due to lack of irrigation and this sensation disappears after a few 
minutes. 
At the end of the MAXIMUM stress test you may feel fatigued. In rare cases, 
dizziness, gastrointestinal disorders and even (in people with undiagnosed heart 
disease) sudden death may be experienced after exertion. If you notice dizziness, 
shortness of breath or sudden pain during this test or the others in this study, you 
should tell us immediately. 


5 
INFORMED CONSENT SHEET 
NAME AND SURNAME 
Date of Birth DNI 
Address 
Telephone contact 
NAME PRINCIPAL INVESTIGATOR RICARDO MORA RODRÍGUEZ 
Exercise Physiology Laboratory. Castilla-La Mancha university. Toledo 
I have read the project information sheet and have had the opportunity to discuss the 
details with the principal investigator and ask him any questions. The person in charge of 
the project has explained to me the purpose of the tests that are going to be carried out 
and I have fully understood everything that has been explained to me. 
I agree to take part in this study and understand that I am completely free to abandon it at 
any time I wish or refuse to perform any of the measurement procedures. 
I understand that the tests carried out are part of a research project that will not bring me 
any personal profit, but that participation is voluntary. The results of this study are 
intended to promote knowledge in Biomedical Sciences and I understand that the 
procedures described have been approved by a clinical research ethics committee. 
I fully and freely consent to participate in the project entitled: INTERACTIONS BETWEEN 
PHYSICAL TRAINING AND MEDICATION IN PATIENTS WITH METABOLIC 
SYNDROME 
Volunteer's Signature 
Place and date 
I confirm that I have explained to the volunteer (named above) the purpose and risks of 
the tests to be carried out. 
Investigator's Signature 
Place and date 
Toledo, 

Prot_000.pdf: 
1 
STUDY TITLE: 
INTERACTIONS BETWEEN PHYSICAL TRAINING AND 
MEDICATION IN PATIENTS WITH METABOLIC SYNDROME 
STUDY PROTOCOL 30 AUGUST, 2017


2 
METHODS 
PRE-POST research project with one ARM (group) and 2 evaluations in each of the 
times in a cross-over randomized fashion. 
Recruitment strategy 
Participants in this research will be recruited through advertisements in the local media 
(newspapers and radio), through which overweight volunteers will be requested 
according to body mass index (BMI <25). From this large pool of potential participants 
who respond to the advertisements, 40 sedentary men and women ages 25-65 who 
meet criteria for metabolic syndrome will be recruited. 
Inclusion and exclusion criteria 
The metabolic syndrome will be defined according to the presence of three of the 
criteria published by the International Diabetes Federation: waist circumference> 94 cm 
for men and> 80 for women of Caucasian ethnicity, high blood pressure figures (> 130 
mmHg for systolic and> 85 for diastolic), high fasting blood glucose (> 100 mg / dl) or 
dyslipidemia: (triglycerides> 150 mg / dl, HDL <40 mg / dl) (1). Participants must be in 
treatment with ARA II hypotensive drugs. All subjects must be physically inactive, at 
least during the previous year according to the criteria of the American College of 
Sports Medicine-ACSM (less than 150 min / week of moderate physical activity or less 
than 75 min / week of vigorous physical activity). 
In addition, participants must not have a diagnosis of any endocrine pathology other 
than carbohydrate intolerance and their hormonal levels (except insulin) must be within 
clinical normal ranges. Other exclusion criteria will be, recent surgery, cardiovascular 
disease (especially uncontrolled coronary disease, heart valve disease, heart failure, 
complex ventricular arrhythmias), diseases with kidney, liver, respiratory or 
neuromuscular involvement. Participants will be informed verbally and in writing of the 
risks and benefits regarding participation in the study and will provide their written 
consent. Participants will be supervised by their family doctors throughout the study. 
Intervention with physical training 
The training program will consist of 3 weekly sessions of interval aerobic exercise 
(EIA). EIA will consist of a cycle ergometer workout (or treadmill running) that includes 
a 10-minute warm-up period at 70% of the peak heart rate (HRpeak) followed by 5 
intervals of vigorous exercise of 4 minutes at 90-95% of your HRpeak interspersed with 
periods of 3 minutes of active recovery at 70% of HRpeak, ending with a 10-minute 
cooldown, reaching a total of 55 min duration per workout. Considering the effects of 
the circadian rhythm on the heart rate, the workouts will be carried out at the same time 
of day and the load will be adjusted daily to provoke the indicated heart rate. Because 
of the adaptations produced by exercise, the training load must be adjusted to reach 
similar heart rates over time and thus comply with the principle of overload for physical 
training. 
Nutritional control 
During the week prior to the start of the interventions, all participants will keep a written 
record of their morning weight (completely naked) and of all food consumed with their 
respective weights. Total energy and macronutrient intake will be evaluated through the 
individual record of each participant using software adapted to the eating habits of 
Spaniards (CESNID Nutritional Calculation Program V 1.0 - Center d'Ensenyament 
Superior de Nutrició I Dietètica assigned to the a University of Barcelona). With these 
data, the usual caloric intake will be established that will be maintained during the 4 
months of intervention to avoid biases due to weight loss resulting from a hypocaloric 


3 
Ejercicio 
o     
Reposo 
Seguimiento durante 3 horas 
Compo 
sición 
corpor 
al 
Presión Arterial 
Gasto Cardiaco 
Presión Arterial 
Gasto Cardiaco 
Presión Arterial 
Gasto Cardiaco 
PORH 
Onda de Pulso 
Presión Arterial 
Gasto Cardiaco 
PORH 
Onda de Pulso 
diet that would confuse the effects of the training program. 
Evaluation procedure 
Participants will go to the laboratory in the morning after an overnight fast and with or 
without their medication depending on the test. In each one the following 
measurements will be made: 
Figure 1. Diagram of the measurements of each of the test. 
8:00 
9:00 
10:00 
12:00
13:00 
Description of the variables to be measured 
Anthropometric measurements and blood pressure at rest 
Weight and height will be evaluated using a standard scale and a stadiometer that 
allows measuring with a precision of 0.1 cm and kg respectively (Seca, Vogel & 
Halke Hamburg, Germany). The body mass index (BMI; in kg / m2) will be calculated 
using the subject's height and weight. The waist circumference (in the horizontal 
plane 2 centimeters below the rib edge (1)) will be measured using a plastic 
measuring tape with a precision of 0.1 cm. 
To measure blood pressure, participants will be seated in a supine position for 15 
min. The systolic (SBP) and diastolic (DBP) blood pressure will then be determined 
with the help of an ambulatory pressure monitor (SunTec Medical, Oscar, USA). The 
average of the last 2-3 measurements will be used as the value of the SBP and DBP. 
Blood pressure during exercise 
During the exercise we will use a specific pressure meter for this situation that not 
only has a very sensitive microphone in the pressure cuff but is also integrated with 
the ECG monitoring through three leads (SunTec Medical, Tango, USA). We will use 
cuffs adjusted to the size of the participant's arm. 


4 
Post-occlusive reactive hyperemia (PORH). 
After 15 minutes of supine rest, participants will have a flush meter placed on the 
skin of the forearm (MoorLab, UK). This flowmeter is simply an adhesive probe that 
with laser technology measures the speed at which the red cells pass through the 
capillary circulation. Once the signal is good, a pressure cuff will be inflated on the 
arm 10 mmHg above the resting systolic pressure. The cuff will remain inflated for 3 
minutes. After this period of circulatory arrest, the pressure cuff will be opened, and 
the flow rate will be measured for 2 minutes. This is a measure of the ability of the 
peripheral vasculature to dilate upon a short-lived ischemic stimulus. 
Pulse wave 
Pulse wave velocity will be measured as an indirect measure of arterial stiffness. For 
this, a tonometer () placed manually in the carotid and femoral arteries will be used 
after having measured the distance between them and with reference to the xyloid 
process. It will be measured sequentially, using the R wave of the electrocardiogram 
as a reference to synchronize the signals. The time interval is measured at the 
beginning of the same, since these points correspond to the beginning of the 
ejection where the possibility of reflections is considered null, the delay being due 
only to the propagation of the wave. 
Blood chemistry analysis 
After a 15-minute supine position and prior to performing the exercise, 10 ml of 
venous blood will be drawn for the analysis of metabolic syndrome factors in blood.  
Thus, plasma glucose, insulin, triglycerides, total cholesterol and HDL-cholesterol 
will be measured. 

SAP_001.pdf: 
1 
STUDY TITLE 
INTERACTIONS BETWEEN PHYSICAL TRAINING AND 
MEDICATION IN PATIENTS WITH METABOLIC SYNDROME 
STATISTICAL ANALYSIS PLAN (30 AUGUST, 2017)


2 
Experimental design and calculation of the sample size. 
The experimental scheme that we propose for this research project does not use a 
parallel control, but the control situation is the PRE training test when the participants 
are oblivious to the exercise adaptations. Therefore, it is an experimental longitudinal 
scheme with repeated measures in the same participants. This greatly reduces 
biological variability since each participant will be compared with himself before and 
after the intervention, which in this case is training. 
In each of the 2 visits where data will be collected for the experiment, four evaluations 
will be carried out following the scheme of isolating or combining our two factors to 
study: a) medication and b) exercise. 
Thus, we will have the following situations: 
a) CONTROL (NO MED, NO TRAIN).  Participants have not started training and their 
habitual antihypertensive medication has been withdrawn for 72 h.
b) MEDICATION.  Participants have not started training and they are taking their 
habitual dose of antihypertensive medication.
b) TRAINED.  Participants have completed the 4 months of aerobic exercise training 
and their habitual antihypertensive medication has been withdrawn for 72 h.
d) EXERCISE + MEDICATION. Participants have completed the 4 months of aerobic 
exercise training and there are taking their habitual antihypertensive medication.
The group will be composed of 40 participants taking into account that the power 
analysis of a study in which similar exercise programs (3 months of duration) were 
used in similar subjects indicates that to observe significant effects on the 
components of the metabolic syndrome, 27 participants were necessary, so we 
propose to recruit 30 to have a 10% lack of adherence to the exercise or diet 
program. 
Statistical analysis 
To evaluate the differences between the PRE-training and POST-training situation, 
repeated measures analysis of variance (ANOVA) will be used, in which the factors 
associated with both medicine withdrawal (MEDIC vs NO-MEDIC) and training 
(TRAINED vs NO-TRAINED) will be analyzed.  Values of P <0.05 will be considered 
significant. Results will be presented as means ± SD.  All statistical analysis will be 
performed using SPSS software (version 19.0