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

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Mayer Davidson, Charles Drew University of Medicine and Science
ClinicalTrials.gov Identifier:
NCT00907374
First received: May 21, 2009
Last updated: March 28, 2012
Last verified: March 2012
  Purpose

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 Intervention
Microalbuminuria
Drug: benazepril

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Early Nephropathy Study in Diabetes With Inhibitory Renin-Angiotensin-Aldosterone System Therapy (END-IT)

Resource links provided by NLM:


Further study details as provided by Charles Drew University of Medicine and Science:

Primary Outcome Measures:
  • Microalbuminuria Reported as Urinary Albumin:Creatinine Ratio [ Time Frame: 3 to 36 months ] [ Designated as safety issue: No ]
    Average of ratio for all participants during the 3-36 months of the study


Secondary Outcome Measures:
  • Estimated Glomerular Filtration Rate [ Time Frame: 3 to 36 months ] [ Designated as safety issue: No ]
    This is an average for all participants during the 3-36 month study period

  • Carotid Artery Intima Thickness [ Time Frame: 6 to 36 months ] [ Designated as safety issue: No ]
    Thickness of intima of right carotid artery; average of all particpants from 6-36 months of study

  • Endothelial Dysfunction [ Time Frame: 6 to 36 months ] [ Designated as safety issue: No ]
    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.


Enrollment: 46
Study Start Date: July 2005
Study Completion Date: April 2009
Primary Completion Date: April 2009 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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

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.

  Eligibility

Ages Eligible for Study:   18 Years to 70 Years
Genders Eligible for Study:   Both
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
Please refer to this study by its ClinicalTrials.gov identifier: NCT00907374

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

No publications provided

Responsible Party: Mayer Davidson, Professor of Medicine, Charles Drew University of Medicine and Science
ClinicalTrials.gov Identifier: NCT00907374     History of Changes
Other Study ID Numbers: IRB# 04-09-772, U54-RR014616
Study First Received: May 21, 2009
Results First Received: February 9, 2012
Last Updated: March 28, 2012
Health Authority: United States: Institutional Review Board

Keywords provided by Charles Drew University of Medicine and Science:
Microalbuminuria
Carotid intima media thickness
Endothelial dysfunction
Renin angiotensin system
Diabetic nephropathy

Additional relevant MeSH terms:
Albuminuria
Proteinuria
Urination Disorders
Urologic Diseases
Urological Manifestations
Signs and Symptoms
Benazepril
Angiotensin-Converting Enzyme Inhibitors
Protease Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Antihypertensive Agents
Cardiovascular Agents
Therapeutic Uses

ClinicalTrials.gov processed this record on April 17, 2014