Clinical Trial Details
— Status: Terminated
Administrative data
| NCT number |
NCT00319202 |
| Other study ID # |
fcv193 |
| Secondary ID |
|
| Status |
Terminated |
| Phase |
Phase 4
|
| First received |
April 26, 2006 |
| Last updated |
November 2, 2012 |
| Start date |
June 2006 |
| Est. completion date |
February 2012 |
Study information
| Verified date |
November 2012 |
| Source |
Fundación Cardiovascular de Colombia |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
Colombia: INVIMA Instituto Nacional de Vigilancia de Medicamentos y Alimentos |
| Study type |
Interventional
|
Clinical Trial Summary
Hypothesis:
The use of candesartan 16-32 mg/d for 6 months improves the carbohydrate metabolism, and
decreases the plasmatic levels of adipocytokines and oxidative stress markers, in non
diabetic, non hypertensive subjects with dysglycemia and abdominal obesity, and these
effects are independent of the changes in arterial blood pressure.
General Objectives:
The objective is to study the impact of the treatment with candesartan in the carbohydrate
metabolism and the plasmatic levels of adipocytokines and oxidative stress markers, in non
diabetic, non hypertensive subjects with dysglycemia and abdominal obesity.
Study Design:
This is a randomized, double blind, cross-over, placebo-controlled, clinical trial to assess
the effects of candesartan (up to 32 mg/d for 6 months), over the carbohydrate metabolism,
plasma levels of adipocytokines and concentrations of oxidative stress markers in non
diabetic, non hypertensive, dysglycemic and obese subjects from Colombia. The total duration
of the study is 36 months.
Population:
One hundred non diabetic, dysglycemic and obese, subjects of both genders, over 18 years
old, will be included. To be included subjects should have blood pressure values under
140/90 mmHg and should be receiving no antihypertensive medical treatment.
Procedures:
Subjects whom fulfill all selection criteria will be included in a run-in period of 15 days
with placebo and hygiene-dietary measures (MHD) including educational, nutritional and
exercise support. The patients that during this "Run in" phase have a compliance equal to or
greater than 80% will be randomized to one of the two treatment groups ("Group A" receiving
candesartan 16/32 mg/d for 6 months and then placebo for 6 months, or "Group B" receiving
placebo during the first 6 months and then candesartan 16/32 mg/d during the last 6 months)
in a 1:1 proportion by blocks of 4 subjects. Randomization will be performed by the
AstraZeneca clinical department. Both groups will concurrently receive the standard
treatment with MHD. Control visits will be programmed every month. Metabolic parameters,
including C-reactive protein (CRP), interleukin-6 (IL-6), adiponectin, leptin, insulin,
malonaldehyde and 8-isoprostanes, will be evaluated every 6 months (at the beginning and end
of each treatment).
Statistical Analysis:
The analysis strategy will be performed by intention-to-treat. In a descriptive analysis,
the averages and proportions will be obtained with their corresponding 95% confidence
intervals for the clinically relevant variables during the baseline evaluation. In order to
evaluate the differences between the groups, the Student's t test, Mann-Whitney and
Fischer's exact tests will be used according to the nature of the study variables. Multiple
lineal regression will be used with the purpose of comparing the treatment groups from
baseline and its changes up to the 6th month of treatment.
Ethical Aspects:
The study will be conducted according to the Helsinki declaration, the good clinical
practices guidelines and the Colombian legislation. Prior to entering the study, patients
must sign a written informed consent that has been approved by the Institutional Ethics
Committee of Fundación Cardiovascular de Colombia.
Description:
Background:
During the last years, the worldwide prevalence of diabetes mellitus type II (DM2) has
increased dramatically, impacting the cardiovascular morbidity and mortality. It has been
estimated that more than 171 million people suffer this disease (2.8% of the worldwide
population) and it's predicted that it will increase to 366 million (6.5 %) in 2030, from
which 298 million will be from developing countries. Currently, in Latin America, the DM2
prevalence ranges are between 1.2% and 8%, and it is expected to increase 38% during the
next 10 years, with higher levels in the urban zones.
Recently, we have demonstrated that the Colombian population with a lower abdominal
circumference than those reported in Caucasian populations presented an increased risk of
developed metabolic syndrome and coronary artery disease. Moreover, abdominal obesity in our
population is associated with higher levels of inflammatory markers, as C-reactive protein
(CRP) and proinflammatory cytokines. Nowadays, the relationship between abdominal obesity,
inflammation, insulin resistance, diabetes mellitus type 2, metabolic syndrome and
cardiovascular disease is a crucial aim of research, especially in populations as the
Colombian, that is in high risk of being affected by the epidemic of diabetes mellitus and
cardiovascular disease. The occurrence of DM2 is associated with a 2 to 4 fold increase in
the risk of developing coronary disease. The diabetic patients that present unstable angina
have a greater risk of developing acute myocardial infarct (AMI) and the diabetic patients
with AMI have more risk of death than the non-diabetic patients. Additionally, the subjects
with DM2 have an increased risk of experiencing cardiovascular events (1.5 to 3 times), and
greater recurrence and mortality for these causes. The incidence and severity of the
peripheral arterial disease are also increased from 2 to 4 times in diabetic patients.
The current criteria for DM2 diagnosis established by the American Association of Diabetes
is a glucose level in fasting >126 mg/dl, which has been established based on the risk of
suffering ophthalmic and renal micro-vascular complications with values superior to this
limit. Nevertheless, several works have shown that patients with altered fasting glucose
levels (≥100 mg/dl - <126 mg/dl) have an increased risk of cardiovascular morbidity and
mortality.
We recently reported in Colombia, the existence of a strong association between the presence
of cardiovascular risk factors and altered fasting plasma glucose, this association being
greater with the presence of abnormal glucose blood levels after the glucose overload test.
This association has been explained since the hyperglycemia per-se may be implicated in the
development of atherosclerosis due to metabolic and structural changes at the endothelial
level. At long term it may result in irreversible alterations; a "non-returning" point
leading to cardiovascular complications typical of diabetes. According to these
observations, our group has recently shown that patients with altered glycemia in fasting,
regardless of other classic factors of cardiovascular risk, present a greater risk of
coronary disease, supporting the hypothesis that the hyperglycemia leads to structural
changes in the endothelial wall.
It is well known that people with insulin resistance present less vasodilatation mediated by
insulin and an altered endothelium dependent vasodilatation. Additionally, it has been
described that insulin causes a physiologic vasodilatation in the skeletal muscle of healthy
subjects, an effect that is blocked in insulin-resistance obesity. In our population, we
find that obesity, hypercholesterolemia and diabetes are related with a flow-mediated
vasodilatation reduction. The endothelial dysfunction is strongly related with the insulin
resistance syndrome. At the same time, the endothelial dysfunction worsens the resistance to
insulin, increases the vascular reactivity and predisposes to cardiovascular disease. It has
been proposed that the vasodilator effect of the insulin is primarily due to a greater
expression of mRNA for endothelial nitric oxide synthase (eNOS) due to a probable increase
of the transcriptional rate. There are elements to support the fact that this activity is
modulated by C-kinase protein (PKC). The inhibition of PKC increases the mRNA levels for
eNOS. Prolonged incubation of endothelial cells with a selective inhibitor of the PKC beta
isoform increase the mRNA levels of eNOS. This observation may have important clinical
implications since the PKC activation in the vasculature of diabetic subjects in alteration
of the vascular wall. The existing relationship between endothelial dysfunction and insulin
resistance is dependent on multiple factors. Obesity generates an alteration of the
endothelial function in the metabolically active capillary bed, altering the lipase
lipoprotein (LPL) that is linked to the endothelium by glycosaminoglycans. The ultimate loss
of these caused by aggressive factors such as smoking and oxygen free radicals, alters the
endothelial function and also impairs the action of the LPL causing hypertriglyceridemia
which is an insulin resistance factor. At the same time, the alteration of endothelial
function in the capillary beds reduces the interstitial flow, carrying less insulin or
delaying its delivery to the muscular tissue. Additionally, it has been proposed that there
is less surface of endothelium functionally normal in the vessels that are irrigating the
skeletal muscle. It has also been shown that hyperinsulinemia predicts the appearance of
atherosclerosis and cardiovascular events, independently of other risk factors.
The increase of adipocytes at the abdominal level is directly related with a condition of
insulin resistance and hyperinsulinism. The hyperinsulinemia promotes the release of free
fatty acids by the adipocyte and its later hepatic transformation to oxidized LDL, which
have a great atherogenic potential. Also, the abdominal adipocytes in response to the
increase of free fatty acids, oxidized LDL or any other non-well defined metabolic factor
increase the production and release of proinflammatory cytokines such as the tumor necrosis
factor alpha (TNF-α) and interleukin-6 (IL-6), which have shown to be able to reduce the
expression and activity of the nitric oxide synthase (eNOS) in human cultivated umbilical
endothelium cells, suggesting that this could be the mechanism by which the abdominal
obesity is related with endothelial dysfunction. In this sense, we have recently
demonstrated that in cultured endothelial cells, the angiotensin II, through receptor AT1,
stimulates the TNF-α production, which at the same time activates the metalloproteinase 2,
enzyme which induces changes in the endothelium structure and in the stability of the
atherosclerotic plaque. This effect of angiotensin II is mediated by the AT1 receptor, since
we have shown that the CANDESARTAN inhibited the production of TNF-α induced by Angiotensin
II.
The increase in the production and storage of free fatty acids may be the mechanism by which
angiotensin II relates with the development of insulin resistance. It has been demonstrated
that the elevated levels of free fatty acids induce insulin resistance through the
inhibition of the transport and phosphorylation of glucose at a muscular level, followed by
a reduction of the glycogen synthesis and glucose oxidation. Additionally, it has been
suggested that free fatty acids may interfere in the stimulation of insulin in the GLUT 4
and hexokinase activity. Also, angiotensin II has a stimulating effect on the transcription
rate of the ob gene in human adipocytes. The ob gene is in charge of codifying the leptin
protein, which inhibits the appetite and regulates the thermogenesis. The chronic and
sustained increase in leptin levels leads to a leptin-resistance condition, a condition in
which the hormone loses its physiological actions. The increase in the leptin levels
produces a greater expression of UPC 2 (Uncoupling protein 2) in an action mediated by
Peroxisome Proliferator-Activated Receptors (PPARs), which interferes with the mitochondrial
respiration chain in the pancreatic beta cells, getting to a reduction in the ATP generation
and blocking the first peak of insulin secretion. This offsetting mechanism seems to be
opposed to the insulin's lipogenic effect and avoids greater lipid storage. Unfortunately,
the derived consequences of this alteration in the insulin secretion are a lower efficacy to
maintain the euglycemia and to maintain a glucidic homeostasis. On the other hand, the
hyperleptinemia, by mediating the sympathetic activity and increasing the sodium renal
resorption, leads to the increases of blood pressure, which adds to the greater expression
of the angiotensinogen produced by hypertrophied lipid cells. These cells generate
angiotensin II to activate the adipocyte differentiation and to regulate the fat storage in
response to nutritional changes.
Recently, some clinical trials have demonstrated that the angiotensin converting enzyme
inhibitors (ACEIs) and ARA II, reduce the risk of presenting new cases of DM2 as compared
with other antihypertensive therapies. However, no clinical trials have addressed
specifically the study of the effects of the ARA II in the improvement of the dysglycemia
and in the prevention of the diabetes type 2. Additionally, the treatment with ACEI and ARA
II has shown to improve the resistance to peripheral insulin both in animal models and
clinical studies. The mechanism by which the renin-angiotensin-aldosterone system blockade
has a beneficial effect on the responsiveness to insulin has not been totally cleared. In
obese Zucker-type rats, it was demonstrated that the chronic treatment with a selective ARA
II receptor produced a significant increase in the GLUT 4 transporter expression in skeletal
muscle and a reduction in the concentrations of plasma fatty acids associated with an
improvement of the responsiveness to insulin.
Although the mechanisms are still speculative, the beneficial effects of the
renin-angiotensin system blockade, demonstrated in several studies such as HOPE, LIFE,
VALUE, on the responsiveness to insulin and in the prevention of the development of new
cases of DM2, suggest that angiotensin II produced in the adipocytes of obese subjects is
associated to the insulin resistance syndrome and supports the execution of clinical trials
oriented to establish the beneficial effect of ARA II in the prevention of DM2 in
susceptible individuals coming from populations at high risk of developing CVD and diabetes
mellitus, as the Colombian one.
Hypothesis:
In non-diabetic non-hypertensive subjects with dysglycemia and abdominal obesity:
The treatment with candesartan 16/32 mg/d during 6 months improves carbohydrate metabolism
measured by HOMA insulin sensibility index, oral glucose tolerance Test (OGTT), fasting
plasma glucose levels, and glycosylated hemoglobin (HbA1c).
The effects of the treatment with candesartan over carbohydrate metabolism is related to a
reduction in the plasma concentration of adipocytokines such as IL-6, CRP, Leptin and
Adiponectin; and oxidative stress markers such as plasma concentrations of Malonaldehyde and
urinary concentration of 8-Isoprostanes.
These effects over carbohydrate metabolism, inflammatory adipocytokines or oxidative stress
markers are independent of changes over arterial blood pressure.
Study Objectives:
General Objectives:
To study the impact of the treatment with candesartan over the carbohydrate metabolism,
inflammatory adipocytokines and levels and oxidative stress markers in non-diabetic
non-hypertensive subjects with dysglycemia and abdominal obesity.
Specific Objectives:
In non-diabetic non-hypertensive subjects with abdominal obesity and dysglycemia:
To establish the impact of the treatment with candesartan (16/32 mg/d) in the carbohydrate
metabolism assessed through the HOMA index, fasting glucose plasma levels, OGTT, and HbA1c
levels.
To study the effects of candesartan 16/32 mg/d during 6 months over fasting plasma levels of
adipocytokines such as Leptin, Adiponectin, IL-6 and CRP.
To determine if the treatment with candesartan (16/32 mg/d during 6 months) decreases the
concentration of oxidative stress markers such as plasma levels of malonaldehyde and urinary
levels of 8-Isoprostanes.
To determine if the effects of candesartan on the carbohydrate metabolism, adipocytokines
and oxidative stress marker concentrations, are independent of its effect upon the blood
pressure.
Study Design:
A randomized, double blind, placebo-controlled, cross-over clinical trial, to assess the
effects of candesartan (16/32 mg/d during 6 months) over metabolic, oxidative, and
inflammatory parameters, in non-diabetic non-hypertensive subjects with dysglycemia and
abdominal obesity.
Study treatments:
Treatment A: Candesartan 16 mg (one tablet per day) taken with breakfast during 4 weeks,
depending on the subject's tolerance the dosage will be increased to 32 mg/d (two tablets)
during the next 20 weeks.
Treatment B: Placebo tablets administered similarly to treatment A (one tablet during 4
weeks and then 2 tablets per day during the next 20 weeks).
All subjects will be included in a hygiene-dietary measures program (MHD; educational,
nutritional and exercise support) during the study.
Study groups:
The study embraces two arms
Group 1: Will receive treatment A first during the first 24 weeks and then treatment B
during the last 24 weeks.
Group 2: Will receive treatment B during the first 24 weeks and then treatment A during the
last 24 weeks.
Population:
The study is going to be integrated by non-diabetic non-hypertensive subjects of both
genders, older than 18 years with abdominal obesity and dysglycemia .
Abdominal obesity is defined as a waist diameter greater than 90 cms in men and 80 cms in
women.
Dysglycemia is defined as having plasma glucose levels in fasting between 100 and 125 mg/dL
and/or on glucose tolerance test at 2 hours between 140 mg/dL and 200 mg mg/dL.
Size of sample:
The size of the sample was estimated considering a crossover, clinical trial design and
following the proposal by Hills and Armitage accepting a type I error of 0.05, a power of
90%, and assuming a difference of 20% in the HOMA index after 6 months of treatment with
candesartan (3 to 2.4) and a maximum standard deviation of 1.5, sample size of 84 subjects
was estimated. By adjusting the rate of losses of 8%, the final sample size is 100 subjects
(50 in each group).
This sample size ensures a power of 90% to detect differences in the fasting glycemia of at
least 8mg/dL (0.44mmol/L), with a standard deviation (SD) of 20mg/dL. (1.1mmol/L) or a
difference of 14mg/dL (0.77mmol/L) in the 2 hours post load glycemia SD of 40mg/dl
(2.2mmol/L).
Statistical Analysis:
The study is fundamentally set forth as an efficacy study on the prevention of the
development of diabetes mellitus and on the changes of the carbohydrate metabolism. The
averages and proportions with their corresponding 95% confidence intervals for clinically
relevant variables measured during the baseline evaluation will be obtained in a descriptive
analysis. In order to evaluate the presence of differences between the groups, the Student's
t test, the Mann-Whitney test, the CHI2 test or the Fisher´s exact test according to the
variable under study will be used. A Linear multiple regression will be used with the
purpose of comparing the treatment groups from baseline and its changes up to month end 6 of
each treatment. The possibility of performing adjustments by required baseline parameters
and risk factors and prior treatment in each one of the treatment groups is considered.
The analysis will be performed by the intention-to-treat approach. A p value under 0.05 will
be considered as statistically significant.The primary endpoint for analysis will be made on
the change in HOMA index value, baseline glucose, and post-charge glucose plasma levels. The
secondary endpoint for analyses will include the possible changes in serum insulin, leptin
and adiponectin, inflammatory markers and oxidative stress markers .
Treatment safety register and analysis will be made through the clinical review and
statistics of the adverse events reported.
Safety Committee and Events Assignation Committee:
A safety and events assignation committee will be created, according to the Harmonized
Tripartite Guidelines of the International Conference of Harmonization for Good Clinical
Practices.
Ethical Aspects:
The clinical trial will be conducted according to the Helsinki's Declaration, Good Clinical
Practice Guidelines and the Colombian legislation (Resolution 8430-93 of the Ministry of
Health). The patient will provide written informed consent in a form designed for such a
purpose.
The information generated by the study will be confidential and strictly used for the
purposes stipulated within the protocol.
Finally, the patient may refuse to continue participating in the study at any moment after
providing his/her consent. The study will be approved by the FVC ethics committee. All
assessments will be performed by trained staff. The blood samples will be collected in
aseptic conditions by an expert bacteriologist.
Study Timeline:
The study period will be 36 months. The initiation will be defined by the project's
financial approval.
