The Effect of Uric Acid Lowering in Type 1 Diabetes

January 11, 2018 updated by: David Z.I. Cherney, University Health Network, Toronto

A Deep Phenotyping Approach to Assess the Effect of Uric Acid Lowering in Patients With Uncomplicated Type 1 Diabetes Mellitus

Patients with type 1 diabetes mellitus (T1DM) are at high risk of developing kidney complications potentially leading to end stage renal disease. Uric acid (UA), the end product of purine metabolism, emerged as an important determinant of renal and vascular injury due to its ability activate the renin-angiotensin-aldosterone system (RAAS) and increase production of harmful reactive oxygen species (ROS). ROS cause progressive endothelial cell dysfunction, inflammation, tissue fibrosis and eventually cell death. These processes are enhanced in DM because of the effect of hyperglycemia.

Since existing preventive drug therapies fail to completely prevent kidney damage, an examination of the effect of UA lowering against initiation and progression of renal and vascular complications is therefore of the utmost importance. The purpose of this study is to examine the effect of UA lowering with febuxostat on renal and systemic vascular function in patients with uncomplicated T1DM. It was hypothesized that UA lowering will improve kidney and systemic vascular function through effects on blood vessel function and anti-inflammatory effect.

Kidney and blood vessel function will be assessed under conditions of normal and high blood sugar levels before and after 8 weeks of treatment with the UA lowering drug febuxostat in patients with diabetes and during normoglycemia only in health controls.

Current treatment for renal and vascular complications in DM patients includes blockade of the RAAS. Unfortunately, angiotensin converting enzyme inhibitors (ACEi) and angiotensin II (AngII) receptor blockers (ARBs) lead to incomplete RAAS suppression, and do not completely prevent renal or vascular complications. Moreover, dual RAAS blockade increases renal and cardiovascular risk. Recent experimental work suggests that UA lowering therapies can block the RAAS, suppress inflammation and promote renal and systemic vascular protection. Therefore, our study is critical in determining the possible role of early UA lowering on renal and systemic hemodynamic dysfunction in young patients with T1DM.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

Uric acid (UA) was recently suggested to exert deleterious effects on blood pressure and renal function, even when baseline UA levels are within the normal range. UA activates the renin angiotensin-aldosterone system (RAAS), increases oxidative stress and promotes inflammation. As a consequence, higher UA levels are associated with metabolic abnormalities (insulin resistance, hyperglycemia), cardiovascular disease (hypertension, endothelial dysfunction, arterial stiffness, cardiac diastolic dysfunction) and kidney function abnormalities (hyperfiltration - a marker for intraglomerular hypertension, proteinuria). Thus pharmacologic UA lowering may promote renal and cardiovascular protection. The mechanisms underlying these protective effects in humans, prior to the onset of clinical disease, remain unknown.

This study is focused on the prevention of complications in young, normotensive type 1 diabetes mellitus (T1DM) patients with normal renal function and UA levels. The study will examine the effect of UA lowering with febuxostat (FBX) on renal hemodynamic function, vascular function and urinary inflammatory biomarkers. Based on substantial supportive pre-clinical and epidemiological data, we hypothesize that lowering UA levels that are within normal range at baseline will: 1) ameliorate hemodynamic abnormalities characteristic of T1DM, and reduce renal and systemic hypertensive responses to hyperglycemia; 2) ameliorate endothelial function abnormalities characteristic of T1DM; 3) reduce urinary inflammatory cytokines/chemokine excretion.

Study Type

Interventional

Enrollment (Actual)

73

Phase

  • Phase 4

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Canada
    • Ontario
      • Toronto, Ontario, Canada, M5G 2N2
        • Renal Physiology Laboratory, University Health Network

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 40 years (ADULT)

Accepts Healthy Volunteers

Yes

Genders Eligible for Study

All

Description

Inclusion Criteria:

  • Age 18-40 years old
  • Normoalbuminuria 24 hour urine collection
  • Body mass index 18-30 kg/m2 at screening
  • Subject able, willing to perform assessments
  • Normal electrocardiogram
  • Normal renal (estimated GFR>60 ml/min)
  • Clinic blood pressure <140/90 mmHg
  • Type 1 DM, duration of diabetes >1 years
  • Able to take medications every day
  • Signed and dated written informed consent on the screening visit in accordance with GCP and local legislation
  • Hemoglobin A1c 6-11%
  • Normal uric acid levels

Exclusion Criteria:

  • Cardiac, lung or peripheral vascular disease or stroke, gout
  • Hypertension, or on BP-lowering medicine
  • History of proliferative retinopathy
  • Diagnosis of brittle diabetes based on investigator judgement
  • Allergy to either allopurinol or probenecid
  • Pregnancy, breastfeeding, no reliable contraception
  • Oral contraceptives (due to effects on the RAS)
  • Alcohol or tobacco within 24 hours prior to the study
  • Uric acid ≥420 μmol/L or taking uric acid lowering agents
  • Use of agents that influence GFR or interfere with purine metabolism (didanosine, azothioprine, methotrexate, NSAIDs, mycophenolate)
  • Pancreas, pancreatic islet cells or renal transplant recipient
  • Medical history of cancer or treatment for cancer in the last five years prior to screening
  • T1DM treatment with any other drugs to reduce blood glucose except insulin within 6 months prior to screening (example: off-label use of metformin)
  • Known autonomic neuropathy and proliferative retinopathy including treated proliferative retinopathy. Subjects with mild non-proliferative diabetic retinopathy can be included
  • Alcohol or drug abuse within the three months prior to informed consent that would interfere with trial participation based on investigator judgement or any ongoing clinical condition that would jeopardize subject safety or study compliance based on investigator judgement
  • ACE inhibitors, angiotensin receptor blockers, direct renin inhibitors, aldosterone antagonists
  • Indication of liver disease, defined by serum levels of either alanine transaminase (ALT) (SGPT), aspartate transaminase (AST) (SGOT), or alkaline phosphatase above 3 x upper limit of normal (ULN) as determined during screening
  • Blood disorders causing hemolysis or unstable red blood cells (e.g. malaria, hemolytic anemia)
  • Pre-menopausal women (last menstruation ≤ 1 year prior to informed consent) who are nursing or pregnant or are of child-bearing potential and are not practising an acceptable method of birth control, or do not plan to continue using this method throughout the study.
  • Participation in another trial with an investigational drug within 30 days prior to informed consent

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: TREATMENT
  • Allocation: NA
  • Interventional Model: SINGLE_GROUP
  • Masking: NONE

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
EXPERIMENTAL: Febuxostat (trade name Uloric®)
Oral tablet, 80mg, OD, 8 weeks
Drug: Febuxostat
Oral tablet, 80mg, OD, 8 weeks
Other Names:
  • Trade name Uloric®

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
The Change in Glomerular Filtration Rate (GFR) After an 8 week Treatment with Febuxostat
Time Frame: Before and after an 8 week treatment with febuxostat.
Glomerular filtration rate (GFR, based on inulin plasma clearance) will be measured in euglycemic and hyperglycemic conditions before and after an 8 week treatment with febuxostat and in response to 1 ng/kg/min and 3 ng/kg/min Angiotensin II infusions in euglycemic conditions before and after 8 weeks of febuxostat administration.
Before and after an 8 week treatment with febuxostat.
The Change in Effective Renal Plasma Flow (ERPF) After an 8 week Treatment with Febuxostat
Time Frame: Before and after an 8 week treatment with febuxostat
Effective Renal Plasma Flow (ERPF, based on paraaminohippurate plasma clearance) will be measured in euglycemic and hyperglycemic conditions before and after an 8 week treatment with febuxostat and in response to 1 ng/kg/min and 3 ng/kg/min Angiotensin II infusions in euglycemic conditions before and after 8 weeks of febuxostat administration.
Before and after an 8 week treatment with febuxostat

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
The Change in Renin Angiotensin Aldosterone System (RAAS) Markers and Neurohormonal Activation After an 8 week Treatment with Febuxostat
Time Frame: Before and after an 8 week treatment with febuxostat.
RAAS and neurohormonal markers will be measured in euglycemic and hyperglycemic conditions before and after an 8 week treatment with febuxostat.
Before and after an 8 week treatment with febuxostat.
The Change in Levels of Vasodilators in Plasma After an 8 week Treatment with Febuxostat
Time Frame: Before and after an 8 week treatment with febuxostat.
Levels of vasodilators will be measured in plasma in euglycemic and hyperglycemic conditions before and after an 8 week treatment with febuxostat.
Before and after an 8 week treatment with febuxostat.
The Change in Blood Pressure After an 8 week Treatment with Febuxostat
Time Frame: Before and after an 8 week treatment with febuxostat.
Blood pressure in euglycemic and hyperglycemic conditions before and after an 8 week treatment with febuxostat and in response to 1 ng/kg/min and 3 ng/kg/min Angiotensin II infusions in euglycemic conditions before and after 8 weeks of febuxostat administration.
Before and after an 8 week treatment with febuxostat.
The Change in Flow Mediated Dilation After an 8 week Treatment with Febuxostat
Time Frame: Before and after an 8 week treatment with febuxostat.
Flow Mediated Dilation will be measured in euglycemic and hyperglycemic conditions before and after an 8 week treatment with febuxostat.
Before and after an 8 week treatment with febuxostat.
The Change in Arterial Stiffness After an 8 week Treatment with Febuxostat
Time Frame: Before and after an 8 week treatment with febuxostat.
Arterial Stiffness will be measured in euglycemic and hyperglycemic conditions before and after an 8 week treatment with febuxostat.
Before and after an 8 week treatment with febuxostat.
The Change in Skin Biopsy Measures of Neurohormonal Activation After an 8 week Treatment with Febuxostat
Time Frame: Before and after an 8 week treatment with febuxostat.
Skin biopsy neurohormonal activation biomarkers will be measured in euglycemic conditions before and after an 8 week treatment with febuxostat.
Before and after an 8 week treatment with febuxostat.

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

University Health Network, Toronto

Collaborators

Canadian Institutes of Health Research (CIHR)
University of Toronto
Toronto General Hospital

Investigators

  • Principal Investigator: David ZI Cherney, MD, PhD, University Health Network, Toronto

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (ACTUAL)

December 18, 2012

Primary Completion (ACTUAL)

September 22, 2015

Study Completion (ACTUAL)

September 22, 2015

Study Registration Dates

First Submitted

January 9, 2015

First Submitted That Met QC Criteria

January 16, 2015

First Posted (ESTIMATE)

January 26, 2015

Study Record Updates

Last Update Posted (ACTUAL)

January 16, 2018

Last Update Submitted That Met QC Criteria

January 11, 2018

Last Verified

January 1, 2018

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 12-5427-A

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

Clinical Trials on Type 1 Diabetes Mellitus

Clinical Trials on Febuxostat

Search Similar Trials

Sponsors and Collaborators

Medical Conditions

Drug Interventions

CROs by country

CROs in Iran

Conditions

Rare Diseases

Drug Interventions

Dietary Supplements

Sponsor/Collaborators

Locations

Subscribe