DETAIL Study: Diabetes Exposed to Telmisartan and Enalapril

Phase 3

Completed

• Conditions: Diabetes Mellitus, Type 2; Hypertension

• Registration Number: NCT00274118
• Lead Sponsor: Boehringer Ingelheim

Brief Summary

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.

Detailed Description

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.

Study Timeline

• Study Start: 1997-07
• Primary Completion: 2004-01
• Study Completion: 2004-01
• Study First Submitted: 2006-01-09
• Study First Submitted QC: 2006-01-09
• Study First Posted: 2006-01-10
• Status Verified: 2013-10
• Last Update Submitted: 2013-10-31
• Last Update Posted: 2013-11-01

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 250

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:

   • Subjects currently treated by diet or diet and oral hypoglycaemic drugs, OR
   • 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):

   • Who were not surgically sterile (tubal ligation, hysterectomy) or
   • 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.
   • 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.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Primary Outcome Measures

Name	Time	Method
Change from baseline in glomerular filtration rate GFR after five years of treatment.	5 years

Secondary Outcome Measures

Name	Time	Method
Change from baseline in GFR after one, two, three and four years of treatment	Baseline, 1,2,3 and 4 years
Change from baseline in creatinine	up to 5 years
Changes in vital signs (DBP, SBP, pulse rate)	up to 5 years
Number of patients with Adverse Events	up to 5 years
Physical examination	up to 5 years
Clinical laboratory parameters	up to 5 years
Incidence of all cause mortality	up to 5 years
Percentage change from baseline in urinary albumin excretion rate	up to 5 years
Incidence of clinical endpoints (including- end-stage renal disease, myocardial infarction, cerebrovascular accident, congestive heart failure)	up to 5 years
Resting 12-lead ECG	up to 5 years

Trial Locations

Locations (20)

Bosch Medicentrum; 🇳🇱 Den Bosch, Netherlands

Hjertelaget Research Foundation; 🇳🇴 Stavanger, Norway

Medical Dept. B0642; 🇩🇰 Hillerød, Denmark

Hvidovre Hospital; 🇩🇰 Hvidovre, Denmark

Gynækologisk/obstetrisk afd.; 🇩🇰 Kolding, Denmark

Department of Respiratory Medicine; 🇬🇧 Birmingham, United Kingdom

Apopleksiafsnittet; 🇩🇰 Frederiksberg, Denmark

Finance Office (Research Unit); 🇬🇧 Newcastle-Upon-Tyne, United Kingdom

Samariterhemmets sjukhus; 🇸🇪 Uppsala, Sweden

Boehringer Ingelheim Investigational Site; 🇬🇧 Pontyclun, United Kingdom

Medicinkliniken; 🇸🇪 Helsingborg, Sweden

Dept. of Diabetes; 🇬🇧 Birmingham, United Kingdom

Lungemedicinsk Forskning; 🇩🇰 Hellerup, Denmark

Lucille Packard Children's Health Services at Stanford; 🇬🇧 Palo Alto, United Kingdom

Kuopion yliopistollinen sairaala, Keuhkoklinikka; 🇫🇮 Kuopio, Finland

Dept. of Internal Medicine; 🇳🇱 Utrecht, Netherlands

Diabetes Centre; 🇬🇧 Rugby, United Kingdom

Diabetes Centre,; 🇬🇧 Nuneaton,, United Kingdom

Northampton General Hospital; 🇬🇧 Northampton, United Kingdom

Royal Bournemouth Hospital; 🇬🇧 Bournemouth, United Kingdom