Official Title: “A Randomised ,Double-Blind ,Parallel-Group Comparison of the Renal and Antihypertensive Effects of Telmisartan and Enalapril in Subjects With Mild to Moderate Hypertension and Concurrent Type II Diabetes Mellitus and Diabetic Nephropathy.”

To compare the renal consequences of two different approaches to blocking the renin angiotensin system in subjects with hypertension and concurrent Type II diabetes mellitus and diabetic nephropathy.

Study Type: Interventional

Study Design: Prevention, Randomized, Double-Blind, Active Control, Parallel Assignment, Efficacy Study

The aims of this study were to compare the renal consequences of two different approaches to blocking the activity of the renin angiotensin system - Angiotensin II antagonism with telmisartan and ACE inhibition with enalapril - in patients with hypertension and concurrent type II diabetes mellitus and diabetic nephropathy.

The study was designed to investigate albumin excretion rates in the short term, and in the longer term, to assess the outcome with respect to maintenance of renal function (GFR) and incidence of clinical endpoints.

Study Hypothesis:

Association of Hypertension and Diabetes Essential hypertension accounts for the majority of hypertension in people with diabetes, particularly in those with type II diabetes, who constitute more than 90% of those with a dual diagnosis of diabetes and hypertension.

Both diabetes and hypertension each confer increased cardiovascular risk, and patients with both conditions have more atherogenic risk factors.

Albumin Excretion as a Therapeutic Marker Microalbuminuria is an early and reliable predictor of diabetic nephropathy in both type I - insulin dependent diabetes mellitus (IDDM) and type II - non insulin dependent diabetes mellitus (NIDDM) patients, nephropathy being characterised by hypertension and an inevitable decline in renal function.

Furthermore, diabetic nephropathy is the single most important cause of end stage renal failure (ESRF) in the western world and over recent years the incidence of ESRF in patients with type II diabetes has dramatically increased.

In addition to predicting nephropathy, in type II diabetes, microalbuminuria also predicts mortality, the major causes of death being related to cardiovascular disease.

Comparison(s):

Selection of an ACE Inhibitor as the Comparative Agent Findings in preclinical studies of animals with diabetes mellitus suggest that ACE inhibitors reduce glomerular damage by one or more mechanisms independent of their antihypertensive effects. Glomerular efferent arteriolar tone is increased in diabetic animals and as a result there is an increase in transcapillary hydraulic pressure. These alterations may decrease the functional integrity of the glomerular capillary wall. In rats with diabetes, the long term administration of an ACE inhibitor diminishes the functional and morphologic evidence of glomerular injury and decreases glomerular transcapillary pressure. Removal of the tonic constrictor effect of angiotensin II on efferent arterioles would be expected to lower glomerular intracapillary pressure while preserving renal plasma flow.

Angiotensin II antagonists appear to be as effective as ACE inhibitors in delaying the progression of renal injury in animal models of diabetes.

Intervention(s) in this Clinical Trial

• Drug: telmisartan
• Drug: enalapril

Primary Measures

• The key variable used to assess renal consequences was glomerular filtration rate (GFR). Change in this parameter after 5 years treatment provided the comparison between the two approaches of blocking the activity of the renin angiotensin system.

Secondary Measures

• Additional variables used to evaluate renal consequences of these two approaches of blocking the activity of the renin angiotensin system included glomerular filtration rates at earlier on-treatment timepoints and urinary albumin excretion rates

INCLUSION CRITERIA

• 1. Male or female subjects between the ages 35 and 80 years.
• 2. Current ACE inhibitor therapy for a minimum period of 3 months prior to study entry.
• 3. Confirmed diagnosis of type II diabetes;
• 1. Subjects currently treated by diet or diet and oral hypoglycaemic drugs, or 2. Subjects currently treated with insulin, with a history of onset of diabetes after the age of 40 and a body weight in excess of ideal body weight at the time of diagnosis, and treated with oral agents for a minimum period of two years.
• 4. On treatment diastolic blood pressure of < 95 mmHg.
• 5. Documentation of a normal renal ultrasound within previous 6 months prior to inclusion (alternate methods eg pyelography, renal isotope method was also acceptable).
• 6. Mean of three consecutive overnight urinary albumin excretion rates > 20 and < 1000
• *g/min at the end of the pre-treatment observation period. (A minimum of two of the three samples must be > 20 *g/min.)
• 7. Glycosylated haemoglobin (HbA 1c) < 10%.
• 8. Serum creatinine < 140 *mol/L.
• 9. Glomerular filtration rate (GFR) > 70 ml/min/1.73 m2.
• 10. Ability to provide written informed consent.

EXCLUSION CRITERIA

• 1. Type I diabetes mellitus.
• 2. Pre-menopausal women (last menstruation < 1 year prior to start of screening period):
• 1. who were not surgically sterile (tubal ligation, hysterectomy) or 2. who were not practising acceptable means of birth control (and do not plan to continue using this method throughout the study). Acceptable methods of birth control include oral, implantable or injectable contraceptives.
• 3. who had a positive serum pregnancy test at baseline.
• 3. Afro Caribbean subjects.
• 4. Mean seated SBP > 180 mmHg.
• 5. Hepatic dysfunction as defined by the following laboratory parameters:
• SGPT(ALT) or SGOT(AST) > 1.5 times the upper limit of normal.
• 6. Known causes of renal dysfunction other than diabetic nephropathy.
• 7. Subjects who had a solitary kidney or known renal artery stenosis.
• 8. NYHA functional class CHF II - IV.
• 9. Known drug or alcohol dependency.
• 10. Subjects receiving any investigational therapy within one month of providing written informed consent.
• 11. Known hypersensitivity to telmisartan or ACE inhibitors or to any component of the formulation.
• 12. Subjects with a history of suspected angioedema related to ACE inhibitor therapy.

Gender Eligibility for this Clinical Trial: Both

Minimum Age for this Clinical Trial: 35 Years

Maximum Age for this Clinical Trial: 80 Years

Are Healthy Volunteers Accepted for this Clinical Trial?: No

Lead Sponsor: Boehringer Ingelheim Pharmaceuticals

Overall Clinical Trial Officials and Contacts

Boehringer Ingelheim Study Coordinator Study Chair Boehringer Ingelheim Ltd./Bracknell  

Information obtained from ClinicalTrials.gov on October 10, 2008

Link to the current ClinicalTrials.gov record. http://clinicaltrials.gov/show/NCT00274118

Study ID Number: 502.236

ClinicalTrials.gov Identifier: NCT00274118

Health Authority: Denmark: Ethics Committee, Sjaellandsgrade 40DK-2200 CPH