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Renal Protective Effect of ACEI and ARB in Primary Hyperoxaluria

Primary Purpose

Hyperoxaluria

Status
Withdrawn
Phase
Phase 3
Locations
Study Type
Interventional
Intervention
ACEI / Angiotensin converting enzyme inhibitor
ARB /Angiotensin Receptor Blocker
Placebo
Sponsored by
Mayo Clinic
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional prevention trial for Hyperoxaluria focused on measuring Primary Hyperoxaluria

Eligibility Criteria

10 Years - 80 Years (Child, Adult, Older Adult)All SexesDoes not accept healthy volunteers

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 -

Sites / Locations

    Arms of the Study

    Arm 1

    Arm 2

    Arm Type

    Active Comparator

    Placebo Comparator

    Arm Label

    1

    2

    Arm Description

    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.

    Patients will take placebo for 24 months.

    Outcomes

    Primary Outcome Measures

    Two-year change in the urinary markers of renal tubular injury and interstitial fibrosis

    Secondary Outcome Measures

    Rate of change in 1. Renal tubular injury markers and 2. Renal function as determined by serum creatinine and creatinine clearance.

    Full Information

    First Posted
    January 19, 2006
    Last Updated
    April 6, 2015
    Sponsor
    Mayo Clinic
    Collaborators
    National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
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    1. Study Identification

    Unique Protocol Identification Number
    NCT00280215
    Brief Title
    Renal Protective Effect of ACEI and ARB in Primary Hyperoxaluria
    Official Title
    Renal Protective Effect of ACEI and ARB in Primary Hyperoxaluria
    Study Type
    Interventional

    2. Study Status

    Record Verification Date
    April 2015
    Overall Recruitment Status
    Withdrawn
    Why Stopped
    Inadequate number of patients, lack of funding
    Study Start Date
    December 2007 (undefined)
    Primary Completion Date
    December 2011 (Actual)
    Study Completion Date
    December 2011 (Actual)

    3. Sponsor/Collaborators

    Name of the Sponsor
    Mayo Clinic
    Collaborators
    National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

    4. Oversight

    Data Monitoring Committee
    No

    5. Study Description

    Brief Summary
    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.
    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.

    6. Conditions and Keywords

    Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
    Hyperoxaluria
    Keywords
    Primary Hyperoxaluria

    7. Study Design

    Primary Purpose
    Prevention
    Study Phase
    Phase 3
    Interventional Study Model
    Parallel Assignment
    Masking
    ParticipantCare ProviderInvestigator
    Allocation
    Randomized
    Enrollment
    0 (Actual)

    8. Arms, Groups, and Interventions

    Arm Title
    1
    Arm Type
    Active Comparator
    Arm Description
    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.
    Arm Title
    2
    Arm Type
    Placebo Comparator
    Arm Description
    Patients will take placebo for 24 months.
    Intervention Type
    Drug
    Intervention Name(s)
    ACEI / Angiotensin converting enzyme inhibitor
    Other Intervention Name(s)
    Lisinopril
    Intervention Description
    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.
    Intervention Type
    Drug
    Intervention Name(s)
    ARB /Angiotensin Receptor Blocker
    Other Intervention Name(s)
    Losartan
    Intervention Description
    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.
    Intervention Type
    Drug
    Intervention Name(s)
    Placebo
    Intervention Description
    Patients will receive placebo for 24 months
    Primary Outcome Measure Information:
    Title
    Two-year change in the urinary markers of renal tubular injury and interstitial fibrosis
    Time Frame
    2 years
    Secondary Outcome Measure Information:
    Title
    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

    10. Eligibility

    Sex
    All
    Minimum Age & Unit of Time
    10 Years
    Maximum Age & Unit of Time
    80 Years
    Accepts Healthy Volunteers
    No
    Eligibility 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 -
    Overall Study Officials:
    First Name & Middle Initial & Last Name & Degree
    Dawn S Milliner, M.D.
    Organizational Affiliation
    Mayo Clinic Hyperoxaluria Center, Rochester MN
    Official's Role
    Principal Investigator

    12. IPD Sharing Statement

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    Links:
    URL
    http://www.ohf.org
    Description
    The Oxalosis and Hyperoxaluria Foundation
    URL
    http://www.mayoclinic.org/hyperoxaluria/
    Description
    Mayo Clinic Hyperoxaluria Center-disease information page

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    Renal Protective Effect of ACEI and ARB in Primary Hyperoxaluria

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