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

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

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]).

Study Overview

• Status: Completed
• Conditions: Microalbuminuria
• Intervention / Treatment: Drug: benazepril; Drug: benazepril

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 46
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • California
    • Los Angeles, California, United States, 90059
      • Charles Drew University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Charles Drew University of Medicine and Science
• Investigators: Principal Investigator: Naureen Taureen, MD, Charles Drew University; Study Director: Mayer B. Davidson, MD, Charles Drew University

Study record dates

Study Major Dates

• Study Start: July 1, 2005
• Primary Completion (Actual): April 1, 2009
• Study Completion (Actual): April 1, 2009

Study Registration Dates

• First Submitted: May 21, 2009
• First Submitted That Met QC Criteria: May 21, 2009
• First Posted (Estimate): May 22, 2009

Study Record Updates

• Last Update Posted (Estimate): March 30, 2012
• Last Update Submitted That Met QC Criteria: March 28, 2012
• Last Verified: March 1, 2012

More Information

Terms related to this study

• Keywords: Endothelial dysfunction; Microalbuminuria; Diabetic nephropathy; Renin angiotensin system; Carotid intima media thickness
• Additional Relevant MeSH Terms: Molecular Mechanisms of Pharmacological Action; Antihypertensive Agents; Enzyme Inhibitors; Protease Inhibitors; Angiotensin-Converting Enzyme Inhibitors; Benazepril
• Other Study ID Numbers: IRB# 04-09-772; U54RR014616 (U.S. NIH Grant/Contract)