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

• ClinicalTrials.gov Identifier: NCT00907374
• Recruitment Status: Completed
• First Posted: May 22, 2009
• Results First Posted: March 30, 2012
• Last Update Posted: March 30, 2012
• Sponsor: Charles Drew University of Medicine and Science
• Information provided by (Responsible Party): Mayer Davidson, Charles Drew University of Medicine and Science

Study Description

Brief Summary:

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]).

Condition or disease	Intervention/treatment	Phase
Microalbuminuria	Drug: benazepril	Not Applicable

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 Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 46 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Early Nephropathy Study in Diabetes With Inhibitory Renin-Angiotensin-Aldosterone System Therapy (END-IT)
• Study Start Date: July 2005
• Actual Primary Completion Date: April 2009
• Actual Study Completion Date: April 2009

Arms and Interventions

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 Name: Lotensin
Experimental: Agressive inhibition of the RAS; 40-80 mg benazepril plus 25-100 mg losartan both orally once or twice daily	Drug: benazepril; 40-80 mg benazepril plus 25-100 mg losartan orally once or twice daily; Other Names: Lotensin; Cozaar

Outcome Measures

Primary Outcome Measures :

1. Microalbuminuria Reported as Urinary Albumin:Creatinine Ratio [ Time Frame: 3 to 36 months ]
   Average of ratio for all participants during the 3-36 months of the study

Secondary Outcome Measures :

1. Estimated Glomerular Filtration Rate [ Time Frame: 3 to 36 months ]
   This is an average for all participants during the 3-36 month study period
2. Carotid Artery Intima Thickness [ Time Frame: 6 to 36 months ]
   Thickness of intima of right carotid artery; average of all particpants from 6-36 months of study
3. Endothelial Dysfunction [ Time Frame: 6 to 36 months ]
   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.

Eligibility Criteria

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

Criteria

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.

Contacts and Locations

Locations

United States, California

Charles Drew University

Los Angeles, California, United States, 90059

Sponsors and Collaborators

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

More Information

• Responsible Party: Mayer Davidson, Professor of Medicine, Charles Drew University of Medicine and Science
• ClinicalTrials.gov Identifier: NCT00907374
• Other Study ID Numbers: IRB# 04-09-772; U54RR014616 ( U.S. NIH Grant/Contract )
• First Posted: May 22, 2009
• Results First Posted: March 30, 2012
• Last Update Posted: March 30, 2012
• Last Verified: March 2012

Keywords provided by Mayer Davidson, Charles Drew University of Medicine and Science:

Microalbuminuria; Carotid intima media thickness; Endothelial dysfunction; Renin angiotensin system; Diabetic nephropathy

Additional relevant MeSH terms:

Benazepril; Angiotensin-Converting Enzyme Inhibitors; Protease Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action; Antihypertensive Agents