Viewing Study NCT00319202



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Study NCT ID: NCT00319202
Status: TERMINATED
Last Update Posted: 2012-11-06
First Post: 2006-04-26

Brief Title: Clinical Trial to Assess the Effects of Candesartan on the Carbohydrate Metabolism of Obese Subjects
Sponsor: Fundación Cardiovascular de Colombia
Organization: Fundación Cardiovascular de Colombia

Study Overview

Official Title: A Randomized Double Blind Cross-Over Placebo-Controlled Clinical Trial to Assess the Effects of Candesartan on the Carbohydrate Metabolism of Non Diabetic Non Hypertensive Subjects With Dysglycemia and Abdominal ObesityARAMIA
Status: TERMINATED
Status Verified Date: 2012-11
Last Known Status: None
Delayed Posting: No
If Stopped, Why?: Difficulties in completing the required sample size
Has Expanded Access: False
If Expanded Access, NCT#: N/A
Has Expanded Access, NCT# Status: N/A
Acronym: ARAMIA
Brief Summary: Hypothesis

The use of candesartan 16-32 mgd 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 mgd 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 14090 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 1632 mgd for 6 months and then placebo for 6 months or Group B receiving placebo during the first 6 months and then candesartan 1632 mgd during the last 6 months in a 11 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 Students t test Mann-Whitney and Fischers 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
Detailed 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 28 of the worldwide population and its predicted that it will increase to 366 million 65 in 2030 from which 298 million will be from developing countries Currently in Latin America the DM2 prevalence ranges are between 12 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 15 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 mgdl 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 mgdl - 126 mgdl 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 insulins 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 1632 mgd 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 1632 mgd in the carbohydrate metabolism assessed through the HOMA index fasting glucose plasma levels OGTT and HbA1c levels

To study the effects of candesartan 1632 mgd during 6 months over fasting plasma levels of adipocytokines such as Leptin Adiponectin IL-6 and CRP

To determine if the treatment with candesartan 1632 mgd 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 1632 mgd 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 subjects tolerance the dosage will be increased to 32 mgd 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 mgdL andor on glucose tolerance test at 2 hours between 140 mgdL and 200 mg mgdL

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 005 a power of 90 and assuming a difference of 20 in the HOMA index after 6 months of treatment with candesartan 3 to 24 and a maximum standard deviation of 15 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 8mgdL 044mmolL with a standard deviation SD of 20mgdL 11mmolL or a difference of 14mgdL 077mmolL in the 2 hours post load glycemia SD of 40mgdl 22mmolL

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 Students t test the Mann-Whitney test the CHI2 test or the Fishers 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 005 will be considered as statistically significantThe 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 Helsinkis 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 hisher 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 projects financial approval

Study Oversight

Has Oversight DMC: None
Is a FDA Regulated Drug?: None
Is a FDA Regulated Device?: None
Is an Unapproved Device?: None
Is a PPSD?: None
Is a US Export?: None
Is an FDA AA801 Violation?: None