Clinical Trial Details
— Status: Completed
Administrative data
| NCT number |
NCT02145611 |
| Other study ID # |
CLAF237ABR07T |
| Secondary ID |
|
| Status |
Completed |
| Phase |
Phase 4
|
| First received |
June 11, 2013 |
| Last updated |
August 15, 2016 |
| Start date |
July 2013 |
| Est. completion date |
May 2016 |
Study information
| Verified date |
August 2016 |
| Source |
Hospital de Base |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
Brazil: National Health Surveillance Agency |
| Study type |
Interventional
|
Clinical Trial Summary
Cardiovascular disease is a major public health problem in our country. Among the causes of
cardiovascular diseases are High Blood Pressure (HBP) and Diabetes Mellitus (DM). Type 2
diabetes (DM2) is associated with a twofold risk of cardiovascular disease, and endothelial
dysfunction is an early marker of vascular complications. There is evidence of action of
glucagon-like peptide 1 (GLP-1) on endothelial cells and vascular smooth muscle.
Vildagliptin is a drug used in the treatment of DM2 able to prolong the activity of GLP-1,
improving glycemic control and endothelial function.
Objectives: To evaluate the effect of vildagliptin on endothelial function in patients with
DM2 and hypertension using the Endo-PAT 2000 device.
Description:
Material and Methods
1. Population Subjects will be selected according these inclusion criteria: aged above 35
years, history of type 2 diabetes and mild hypertension (blood pressure < 160 X 100
mmHg) no longer than 15 years, body mass index < 35 Kg/m2, and glycated hemoglobin
(HbA1c) between 7,0 e 10,5%. Exclusion criteria are: smoking within the last six
months, pregnancy or breastfeeding; creatinine clearance < 45 ml/min/m2 (MDRD); use of
NPH (neutral protamine Hagedorn) or/and regular insulin, pioglitazone, GLP-1 receptor
agonist, DPP-4 inhibitor or acarbose; a serum alanine aminotransferase or aspartate
aminotransferase level of more than 3 times the upper limit of the normal range;
subjects with ischemic heart disease, cerebrovascular disease, other atherosclerotic
disease, cancer, or heart failure in functional classes II, III and IV; stress test
with typical chest pain or with ST segment depression ≥ 1 mm, with horizontal or
descendent and duration of 0.08 seconds after the J point; use of 3 or more anti
hypertensive drugs, which characterizes a resistance hypertension; intolerance to
metformin, and inability to give informed consent.
1.2 Sample size To calculate the number of patients we used the site:
www.lei.dante.br-pesquisa. The sample will be composed of 25 patients in each arm. The
number of patients per group necessary to detect a difference in reactive hyperemia
index (RHI) of 0.3 with a power of 80% is 25 patients. And with a two-tailed t test at
the 5% level it was calculated to be 21, with SD of 0.35 for the difference in RHI. The
RHI improvement by 0.3 was based on previous study and a drop out rate of 20% was
considered.
Fifty diabetic and hypertensive patients will be randomized at first visit, submitted
to endothelial function testing by the Endo-PAT 2000 device, and divided into 2 groups:
group 1 will receive vildagliptin (100 mg/day, divided in 2 times) added-on to
metformin (500 to 2550 mg/day, according to glycemic control) and group 2 will receive
glibenclamide (5 to 20 mg/day, according to glycemic control) added-on to metformin.
Blood samples will be collected after 12-hour overnight fast at screening visit and 12
weeks after treatment with vildagliptin (group 1) and glibenclamide (group 2).
At screening, renin angiotensin system blockers will be added for all subjects, and
other antihypertensive drugs will be maintained. All patients will give informed
consent after the study be approved by the local Institutional Review Board.
1.3 Blood Pressure The blood pressure (BP) measurement technique will be made according
VI Brazilian Guidelines to Hypertension Treatment: 1) measurements were taken with a
recently calibrated aneroid sphygmomanometer known to be accurate; 2) the cuff was
placed so that the lower edge was 3 cm above the elbow crease and the bladder was
centered over the brachial artery; 3) a standard bladder was used (12-13 cm long and 35
cm wide), but a larger and a smaller bladder were available for thicker and thinner
arms, respectively; 4) the arm was bare and supported with the blood pressure cuff
positioned at heart level; 5) the mean of three BP measurements taken in the sitting
position after 5 to 10 minutes of rest was used; 6) phase I and V (disappearance)
Korotkoff sounds were used to identify systolic and diastolic BP, respectively; 7) the
pressure was increased rapidly to 30 mmHg above the level at which the radial pulse was
extinguished; 8) a cuff deflation rate of 2 mmHg per beat was used; 9) a minimum of
1-minute intervals were recommended between readings to avoid venous congestion; 10) BP
was measured in both arms to detect possible differences due to peripheral vascular
disease; in this case, the higher value was taken as the reference one. Hypertension is
defined as systolic BP ≥ 140 mmHg and/or diastolic BP ≥ 90 mmHg or current use of
anti-hypertensive drugs.
1.3 Anthropometric Measure Weight and height will be measured by anthropometric scale
and body mass index (BMI) will obtained by the formula: BMI = weight (Kg) / (height in
meters)2.
1.4 Randomisation A computer-generated randomisation list will be delivered by the
Research Center of the glibenclamide/vildagliptin group.
2. Laboratory Blood sample will be drawn after 12 hours fast to measure triglycerides,
total cholesterol and HDL-cholesterol, glycemia, serum creatinine, ultrasensitive
reactive C protein (RCP), Alanine aminotransferase and HbA1c. Microalbuminuria also
will be evaluated. Diabetic subjects will be identified by history of diabetes with
dietetic treatment for diabetes or in use of hypoglycemic drugs. Subjects will be
considered diabetic after 2 fasting glucose more than 125 mg/dl, according with
National Diabetes Data Group. Serum cholesterol will be evaluated according Brazilian
Guideline of Dyslipidemia. Low density lipoprotein cholesterol (LDLc) will be
calculated by the Friedewald formula for triglycerides (TG) levels below 400 mg/dL (
LDLc = TC - HDLc - TG/5 (para TG < 400 mg/dL).
Total Cholesterol (TC); high density lipoprotein cholesterol (HDLc).
3. Treadmill test At screening visit all selected subjects will be submitted for coronary
disease evaluation by stress test. Subjects with stress test with typical chest pain or
with ST segment depression ≥ 1 mm, with horizontal or descendent and duration of 0.08
seconds after the J point will be excluded.
4. Endothelium function Pulse amplitude tonometry (Endo-PAT 2000; Itamar Medical,
Caesarea, Israel) is a peripheral endothelium function test, a non-invasive
determination of digital endothelium function. This test will be performed following a
light breakfast in the morning after 20 min rest and with the patient in a supine
position. The PAT device is placed on the tip of each index finger and comprises a
pneumatic pletysmography that applies a uniform pressure to the surface of the distal
finger, allowing measurement of pulse volume changes. The inflation pressure of the
digital device is electronically set to 10 mmHg below diastolic blood pressure or 70
mmHg. The PAT signal is recorded at baseline and following 5 min arterial occlusion
using a inflatable cuff, while the contralateral arm serves as a control. The blood
pressure cuff is inflated to 60 mmHg higher than systolic pressure or at least 200 mmHg
for 5 min. Lack of residual pulsatility is monitored throughout the occlusion period.
The post-occlusive hyperemia stimulates endothelium-dependent vasodilatation, causing
an increase in digital pulse amplitude. Pulse amplitude is recorded electronically in
both fingers and analysed by a computerised, automated algorithm (Itamar Medical). The
change from the baseline measurement is expressed as the reactive hyperemia index
(RHI), which in part reflects vasodilator function of the digital microcirculation.
Subjects will be instructed to fast starting the night before testing and to refrain
from ingesting alcohol or caffeine. Room temperature will be maintained at all time
during the study between 21º C and 24° C; restrictive clothing that could interfere
with blood flow to the arms, watches or rings or other jewellery on the hands will be
removed. The patient will be comfortably seated or allowed to lie down in the study
room for at least 15 min to reach a relaxed cardiovascular steady-state.
The subjects for the study will be submitted to the endothelium function test at first
visit and 12 weeks after treatment. Endothelial dysfunction is defined as 2.34±0.33
less than 2 standard deviations (SD) of 20 healthy asymptomatic control individuals
without history of cardiovascular disease and without major risk factors, corresponding
to RHI ≤ 1,6837.
5. Central Arterial Pressure The applanation tonometry from the radial artery is a
non-invasive method assessing arterial stiffness, which is predictive of vascular
disease. A portion of the artery pressure wave travelling towards the extremities is
reflected back from peripheral impedance points. In healthy individuals, the reflected
wave returns to the aorta during diastole. When arteries become stiff, the transit time
for de incident and reflected waves is reduced. Thus, the reflected wave returns to the
aorta during systole of the same cardiac cycle augmenting the central blood pressures.
This augmenting of central pressure can be quantified by augmentation index (AIx). AIx
has been associated with cardiovascular risk, predicts the presence or absence of
coronary artery disease40. Higher values of AIx indicate increased wave reflection from
periphery or earlier return of the reflected wave as a result of increased pulse
velocity, which can be contributed to an increased arterial stiffness. In young healthy
individuals, the systolic arterial pressure (aortic) is about 20 mmHg less than the
peripheral systolic pressure (brachial).
The applanation tonometry from the radial artery will be performed in the randomised
subjects at the first visit and 12 weeks after the treatment.
Statistical analysis The continuous variables will be analyzed using the Student's t-test
and analysis of variance (ANOVA). Data will be presented as mean ± 1 SD for continuous
variables and as frequencies for categorical variables. The chi-squared test will be
utilized for the comparative study between the groups in use of vildagliptin with those in
use of glibenclamide. Logistical regression will be performed for associations with
statistical significance. An alpha error of 5% was considered acceptable giving significance
with p-value<0.05.
Pharmacovigilance requirements:
Any serious adverse events will be reported to the Ethics Committee of the FAMERP within 24
hours of the occurrence. All serious adverse events will also be reported to Novartis Drug
Safety & Epidemiology (DS&E) within 24 hours of the investigator (or designee) being aware
of the serious adverse event. Specific definitions of adverse events, and serious adverse
events, are outlined below, along with reporting criteria required by Novartis.
Adverse events (AE) Information about all AEs, whether volunteered by the patient,
discovered by investigator questioning, or detected through physical examination, laboratory
test or other means, will be collected and recorded on an Adverse Event Case Report Form and
will be followed up as appropriate.
An AE is any undesirable sign, symptom or medical condition occurring after starting study
treatment, even if the event is not considered to be treatment-related. Study treatment
includes the study medication under evaluation, and any reference or placebo drug (or
therapy) given during any phase of the trial.
Medical conditions/diseases present before starting study treatment will only be considered
adverse events if they worsen after starting study treatment (any procedures specified in
the protocol). Adverse events (but not serious adverse events) occurring before starting
study treatment but after signing the informed consent form will be recorded on the Medical
History/Current Medical Conditions Case Report Form. Abnormal laboratory values or test
results constitute adverse events only if they induce clinical signs or symptoms, are
considered clinically significant or require therapy, and are recorded on the Adverse Events
Case Report Form under the signs, symptoms or diagnosis associated with them.
As far as possible, each adverse event will also be described by:
1. its duration (start and end dates),
2. the severity grade (mild, moderate, severe),
3. its relationship to the study drug (suspected / not suspected),
4. the action(s) taken.
