Renal Protective Effect of ACEI and ARB in Primary Hyperoxaluria - Full Text View

Sponsor:	Mayo Clinic
Collaborator:	National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Information provided by:	Mayo Clinic
ClinicalTrials.gov Identifier:	NCT00280215

Sponsor:

Mayo Clinic

Collaborator:

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Information provided by:

Mayo Clinic

ClinicalTrials.gov Identifier:

NCT00280215

Purpose

This study will test the effectiveness of two medications: ACEI (angiotensin converting enzyme inhibitor)and ARB (angiotensin receptor blocker) in reducing the renal injury induced by hyperoxaluria in patients with Primary Hyperoxaluria.

Hypothesis: Calcium oxalate crystal deposition in the kidney causes inflammation and resulting injury to kidney tissue. Angiotensin blockade will improve these changes, thus slowing the progression of renal insufficiency in patients with Primary Hyperoxaluria.

Condition	Intervention	Phase
Hyperoxaluria	Drug: ACEI / Angiotensin converting enzyme inhibitor Drug: ARB /Angiotensin Receptor Blocker Drug: Placebo	Phase III

Study Type:	Interventional
Study Design:	Allocation: Randomized Endpoint Classification: Efficacy Study Intervention Model: Parallel Assignment Masking: Double Blind (Subject, Caregiver, Investigator) Primary Purpose: Prevention
Official Title:	Renal Protective Effect of ACEI and ARB in Primary Hyperoxaluria

Resource links provided by NLM:

Genetics Home Reference related topics: primary hyperoxaluria

Drug Information available for: Lisinopril Losartan Losartan potassium

U.S. FDA Resources

Further study details as provided by Mayo Clinic:

Primary Outcome Measures:

Two-year change in the urinary markers of renal tubular injury and interstitial fibrosis [ Time Frame: 2 years ] [ Designated as safety issue: No ]

Secondary Outcome Measures:

Rate of change in 1. Renal tubular injury markers and 2. Renal function as determined by serum creatinine and creatinine clearance. [ Time Frame: 2 years ] [ Designated as safety issue: No ]

Estimated Enrollment:	40
Study Start Date:	December 2007
Estimated Study Completion Date:	December 2011
Estimated Primary Completion Date:	December 2011 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
Active Comparator: 1 Patients will be randomized to a combination of Angiotensin Converting Enzyme Inhibitor and Angiotensin Receptor Blocker. Patients will be randomized to a combination of ARB(losartan 50 mg daily in adult patients, 0.7 mg/kg/day in patients < 40 kg) ACE-I (lisinopril 10 mg daily in adult patients, 0.15 mg/kg/day in pediatric patients < 40 kg) to be taken for 24 months.	Drug: ACEI / Angiotensin converting enzyme inhibitor Patients will be randomized to a combination of Angiotensin Converting Enzyme Inhibitor and Angiotensin Receptor Blocker, Patients will be randomized to a combination of ARB(losartan 50 mg daily in adult patients, 0.7 mg/kg/day in patients < 40 kg) ACE-I (lisinopril 10 mg daily in adult patients, 0.15 mg/kg/day in pediatric patients < 40 kg) to be taken for 24 months. Other Name: Lisinopril Drug: ARB /Angiotensin Receptor Blocker Patients will be randomized to a combination of Angiotensin Converting Enzyme Inhibitor and Angiotensin Receptor Blocker,Patients will be randomized to a combination of ARB(losartan 50 mg daily in adult patients, 0.7 mg/kg/day in patients < 40 kg) ACE-I (lisinopril 10 mg daily in adult patients, 0.15 mg/kg/day in pediatric patients < 40 kg) to be taken for 24 months. Other Name: Losartan
Placebo Comparator: 2 Patients will take placebo for 24 months.	Drug: Placebo Patients will receive placebo for 24 months

Arms

Assigned Interventions

Active Comparator: 1

Patients will be randomized to a combination of Angiotensin Converting Enzyme Inhibitor and Angiotensin Receptor Blocker. Patients will be randomized to a combination of ARB(losartan 50 mg daily in adult patients, 0.7 mg/kg/day in patients < 40 kg) ACE-I (lisinopril 10 mg daily in adult patients, 0.15 mg/kg/day in pediatric patients < 40 kg) to be taken for 24 months.

Drug: ACEI / Angiotensin converting enzyme inhibitor

Patients will be randomized to a combination of Angiotensin Converting Enzyme Inhibitor and Angiotensin Receptor Blocker, Patients will be randomized to a combination of ARB(losartan 50 mg daily in adult patients, 0.7 mg/kg/day in patients < 40 kg) ACE-I (lisinopril 10 mg daily in adult patients, 0.15 mg/kg/day in pediatric patients < 40 kg) to be taken for 24 months.

Other Name: Lisinopril

Drug: ARB /Angiotensin Receptor Blocker

Patients will be randomized to a combination of Angiotensin Converting Enzyme Inhibitor and Angiotensin Receptor Blocker,Patients will be randomized to a combination of ARB(losartan 50 mg daily in adult patients, 0.7 mg/kg/day in patients < 40 kg) ACE-I (lisinopril 10 mg daily in adult patients, 0.15 mg/kg/day in pediatric patients < 40 kg) to be taken for 24 months.

Other Name: Losartan

Placebo Comparator: 2

Patients will take placebo for 24 months.

Drug: Placebo

Patients will receive placebo for 24 months

Detailed Description:

In patients with primary hyperoxaluria (PH), deficiency of hepatic enzymes important in disposition of glyoxylate results in marked hyperoxaluria. Calcium oxalate crystals and high oxalate concentrations in the renal filtrate result in inflammation and injury in the renal parenchyma. Loss of renal function over time is characteristic, with end stage renal failure occurring in half the patients by age 35 years, but as early as infancy in some patients. Experience in animal models of hyperoxaluria, and from other renal diseases, supports a role for ACEI and ARB medications in ameliorating inflammation and injury thus providing a renal protective effect.

We propose to study the short-term effect of combined angiotensin converting enzyme inhibitor (ACEI) and angiotensin receptor blocking (ARB) therapy in patients with PH, in a controlled, randomized, two-year study. Primary endpoints will be urinary markers of renal tubular injury (retinol binding protein (RBP), alpha 1 microglobulin (α1m), γ-glutamyl transferase (GGT)) and interstitial fibrosis (transforming growth factor beta 1 (TGFβ1). Secondary endpoints will be the rates of change in renal tubular injury and renal function as determined by serum creatinine and creatinine clearance.

Eligibility

Ages Eligible for Study:	10 Years to 80 Years
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

Diagnosis of PH established by liver enzyme analysis in the patient or an affected sibling, DNA testing for mutations of the AGXT and GR/HPR gene, or meeting clinical criteria (Urine oxalate > 70 mg/1.73 m2/day in the absence of malabsorption or dietary excess of oxalate. Elevated urine glycolate or glycerate provides supporting evidence of type I or type II PH, respectively).
Hyperoxaluria that persists during treatment with pyridoxine.
Ten years of age or older.
Glomerular filtration rate > 50 ml/min/1.73 m2 at the start of the study.
Women of child bearing age will be required to use adequate contraception for 3 months before and throughout the study.
Patients will be on a stable program of pyridoxine, neutral phosphate, or citrate medications -

Exclusion Criteria:

a. Age < 10 years. b. Glomerular filtration rate < 50 at start of study c. Hypersensitivity to ACEI or ARB medications d. Chronic use of ACEI or ARB medications prior to enrollment e. Hyperkalemia f. Previous renal transplant g. Homozygosity for the G170R mutation of AGXT h. Unwillingness to use adequate contraception during the study. i. Pregnancy

Responsible Party:	Dr. Dawn S. Milliner, Mayo Clinic, Rochester MN
ClinicalTrials.gov Identifier:	NCT00280215 History of Changes
Other Study ID Numbers:	2203-05, NIH grant # DK 73354
Study First Received:	January 19, 2006
Last Updated:	July 8, 2010
Health Authority:	United States: Federal Government