Low Dose Versus Aggressive Inhibition of the Renin-Angiotensin-Aldosterone (RAS) to Treat Microalbuminuria

Study Overview
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Brief Summary
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The objective of the study is to assess the effect of standard versus aggressive inhibition of the renin-angiotensin system (RAS)in type 2 diabetic patients with microalbuminuria (MA) on; a)progression of microalbuminuria, b)estimated glomerular filtration rate (eGFR), c)endothelial dysfunction (measured by post-hyperemia arterial tonometry) and d)the slowing of the progression of atherosclerotic disease (measured by carotid intima media thickness [CIMT]).

Detailed Description
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Diabetic patients with confirmed MA (50-300 mg albumin per g creatinine) on a morning spot urine sample were entered into a one to three month run-in phase before randomization. (50 mg/g was used as the lower limit to allow room for improvement to reach normal.) Since hypertension and uncontrolled hyperglycemia will cause MA, blood pressure (BP) and hemoglobin A1c (AIC) levels were reduced to <130/80 mm Hg and <8.0%, respectively, during this period. All patients had been on various doses of an angiotensin converting enzyme inhibitor (ACE-I) which were reduced to 10 mg benazepril and BP controlled with other classes of anti-hypertensive drugs (except for angiotensin receptor blockers [ARB's]). Glycemia was treated with intensification of their current therapy. MA and BP were measured monthly. When goal levels of BP and AIC were achieved and MA was still present, patients were randomized to either low dose RAS inhibition (10 mg benazepril) (Standard) or aggressive inhibition of the RAS (Aggressive). MA continued to be measured monthly and the progressive increase in doses of an ACE-I and an ARB was as follows. Benazepril (the ACE-I) - 10 mg to 20 mg to 40 mg to adding losartan (the ARB) -25 mg to 50 mg to 100 mg to increasing benazepril to 80 mg with the goal of returning albumin excretion to normal. Other classes of drugs were reduced as necessary to keep systolic BP > 100 mm Hg. Serum creatinine and potassium[K+] were measured monthly, AIC levels every 3 months and CIMT by ultrasound and endothelial function by post hyperemia and nitroglycerine (NTG) - induced peripheral artery tonometry (PAT) via finger plethysmography every six months.

Official Title
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Early Nephropathy Study in Diabetes With Inhibitory Renin-Angiotensin-Aldosterone System Therapy (END-IT)

Conditions
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Microalbuminuria

Intervention / Treatment
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* Drug: benazepril
* Drug: benazepril


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Males and females, age 18-70 Subjects with diabetic renal disease as defined by spot urine albumin - creatinine ratio 30-300mg/g and estimated glomerular filtration rate of >60 ml/min Exclusion Criteria: Intake of non-steroidal anti-inflammatory agents (NSAIDs) more than 15 days/month, excluding aspirin. Inability to discontinue NSAIDs or aspirin for 5 days prior to GFR measurement. History of severe adverse reaction to any of the randomized drugs required for use in the protocol or contraindication of their use. Participation in another intervention study. Pregnancy or likelihood of becoming pregnant during the study period; lactation Clinical and laboratory evidence of any renal disease other than diabetic nephropathy. History of drug abuse in the past 2 years, including narcotics, cocaine or alcohol (> 21 drinks per week). Serious systemic disease that might influence survival or the course of renal disease. (Chronic oral steroid therapy is exclusion, but steroid-containing nasal sprays are not. Inactive sarcoidosis is not an exclusion). History of malignant or accelerated hypertension within 6 months prior to study entry; previous chronic peritoneal or hemodialysis or renal transplantation. Known secondary causes of hypertension. Spot urine albumin - creatinine ratio exceeding 300 (mg/g) Serum potassium level > 5.5 mEq/L for those not on ACE inhibitors during Baseline, or serum potassium level > 5.9 mEq/L for those on ACE inhibitors during Baseline. Leukopenia < 2,500/mm3 at screening and confirmed at the end of Baseline. Doubt that the participant will be able to adhere to medications or comply with the protocol visit schedule Arm Circumference > 52 cm, which precludes measuring blood pressure with the thigh blood pressure cuff. Arm length such that if the cuff circumference extended into the antecubital space so that the cuff interfered with placement of the stethoscope over the brachial artery for blood pressure measurement Clinical evidence of lead intoxication. Clinical evidence of congestive heart failure, current or within the preceding six months. Ejection fraction below 35% measured by any method. Heart block greater than first degree or any other arrhythmia that contraindicated the use of any of the primary BP drugs.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Low dose inhibition of RAS<br>Standard low dose inhibition of the RAS with 10 mg of benazepril orally daily to treat microalbuminuria | Drug: benazepril<br>* benazepril 10 mg orally once daily<br>* Other names: Lotensin;|
| Experimental: Agressive inhibition of the RAS<br>40-80 mg benazepril plus 25-100 mg losartan both orally once or twice daily | Drug: benazepril<br>* 40-80 mg benazepril plus 25-100 mg losartan orally once or twice daily<br>* Other names: Cozaar;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Microalbuminuria Reported as Urinary Albumin:Creatinine Ratio | Average of ratio for all participants during the 3-36 months of the study | 3 to 36 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Estimated Glomerular Filtration Rate | This is an average for all participants during the 3-36 month study period | 3 to 36 months | 
| Carotid Artery Intima Thickness | Thickness of intima of right carotid artery; average of all particpants from 6-36 months of study | 6 to 36 months | 
| Endothelial Dysfunction | Post hyperemia increase in blood flow - fold increase from before and after occluding BP; values are mean of all participants in 6-36 months of study period. | 6 to 36 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Microalbuminuria, Carotid intima media thickness, Endothelial dysfunction, Renin angiotensin system, Diabetic nephropathy