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

Microalbuminuria Clinical Trial

— END-IT  

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00907374
• Other study ID #: IRB# 04-09-772
• Secondary ID: U54RR014616
• Status: Completed
• Phase: N/A
• First received: May 21, 2009
• Last updated: March 28, 2012
• Start date: July 2005
• Est. completion date: April 2009

Study information

• Verified date: March 2012
• Source: Charles Drew University of Medicine and Science
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Institutional Review Board
• Study type: Interventional

Clinical Trial 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]).

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 46
• Est. completion date: April 2009
• Est. primary completion date: April 2009
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years to 70 Years

Eligibility

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 Design

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Albuminuria
• Microalbuminuria

Intervention

Drug:
• benazepril
benazepril 10 mg orally once daily
• benazepril
40-80 mg benazepril plus 25-100 mg losartan orally once or twice daily

Locations

Country	Name	City	State
United States	Charles Drew University	Los Angeles	California

Sponsors (1)

Lead Sponsor	Collaborator
Charles Drew University of Medicine and Science

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	No
Secondary	Estimated Glomerular Filtration Rate	This is an average for all participants during the 3-36 month study period	3 to 36 months	No
Secondary	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	No
Secondary	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	No