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The Effect of Uric Acid Lowering in Type 1 Diabetes

Primary Purpose

Type 1 Diabetes Mellitus

Status

Completed

Phase

Phase 4

Locations

Canada

Study Type

Interventional

Intervention

Febuxostat

About this trial

This is an interventional treatment trial for Type 1 Diabetes Mellitus focused on measuring Diabetic Nephropathy, Diabetes Mellitus, Diabetes Complications, Uric Acid, Febuxostat, Uloric, Glomerular Filtration Rate, Kidney Disease, Vascular Disease, Cardiovascular Diseases, Endothelial Function, Arterial Stiffness, Pharmacologic Actions, Gout Suppressants, Therapeutic Uses, Free Radical Scavengers, Antioxidants, Protective Agents, Physiological Effects of Drugs, Angiotensin II Infusion, Flow-mediated Dilation, Flow-mediated Constriction, Nitroglycerin, Hyperglycemia, Renin-angiotensin-aldosterone System, Nitric Oxide, cGMP, Oxidative Stress, Renal Haemodynamic Function, Inulin Clearance, PAH Clearance, Skin Biopsy, T1R mRNA Expression, Cytokines, Chemokines

Eligibility Criteria

18 Years - 40 Years (Adult)All SexesAccepts Healthy Volunteers

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

Sites / Locations

Renal Physiology Laboratory, University Health Network

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Febuxostat (trade name Uloric®)

Arm Description

Oral tablet, 80mg, OD, 8 weeks

Outcomes

Primary Outcome Measures

The Change in Glomerular Filtration Rate (GFR) 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.

The Change in Effective Renal Plasma Flow (ERPF) 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.

Secondary Outcome Measures

The Change in Renin Angiotensin Aldosterone System (RAAS) Markers and Neurohormonal Activation 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.

The Change in Levels of Vasodilators in Plasma 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.

The Change in Blood Pressure 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.

The Change in Flow Mediated Dilation 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.

The Change in Arterial Stiffness 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.

The Change in Skin Biopsy Measures of Neurohormonal Activation 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.

Full Information

NCT ID

NCT02344602

First Posted

January 9, 2015

Last Updated

January 11, 2018

Sponsor

University Health Network, Toronto

Collaborators

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

1. Study Identification

Unique Protocol Identification Number

NCT02344602

Brief Title

The Effect of Uric Acid Lowering in Type 1 Diabetes

Official Title

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

Study Type

Interventional

2. Study Status

Record Verification Date

January 2018

Overall Recruitment Status

Completed

Study Start Date

December 18, 2012 (Actual)

Primary Completion Date

September 22, 2015 (Actual)

Study Completion Date

September 22, 2015 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Principal Investigator

Name of the Sponsor

University Health Network, Toronto

Collaborators

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

4. Oversight

Data Monitoring Committee

5. Study Description

Brief Summary

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.

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.

6. Conditions and Keywords

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

Type 1 Diabetes Mellitus

Keywords

Diabetic Nephropathy, Diabetes Mellitus, Diabetes Complications, Uric Acid, Febuxostat, Uloric, Glomerular Filtration Rate, Kidney Disease, Vascular Disease, Cardiovascular Diseases, Endothelial Function, Arterial Stiffness, Pharmacologic Actions, Gout Suppressants, Therapeutic Uses, Free Radical Scavengers, Antioxidants, Protective Agents, Physiological Effects of Drugs, Angiotensin II Infusion, Flow-mediated Dilation, Flow-mediated Constriction, Nitroglycerin, Hyperglycemia, Renin-angiotensin-aldosterone System, Nitric Oxide, cGMP, Oxidative Stress, Renal Haemodynamic Function, Inulin Clearance, PAH Clearance, Skin Biopsy, T1R mRNA Expression, Cytokines, Chemokines

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 4

Interventional Study Model

Single Group Assignment

Masking

None (Open Label)

Allocation

N/A

Enrollment

73 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Febuxostat (trade name Uloric®)

Arm Type

Experimental

Arm Description

Oral tablet, 80mg, OD, 8 weeks

Intervention Type

Drug

Intervention Name(s)

Febuxostat

Other Intervention Name(s)

Trade name Uloric®

Intervention Description

Oral tablet, 80mg, OD, 8 weeks

Primary Outcome Measure Information:

Title

The Change in Glomerular Filtration Rate (GFR) After an 8 week Treatment with Febuxostat

Description

Time Frame

Before and after an 8 week treatment with febuxostat.

Title

The Change in Effective Renal Plasma Flow (ERPF) After an 8 week Treatment with Febuxostat

Description

Time Frame

Before and after an 8 week treatment with febuxostat

Secondary Outcome Measure Information:

Title

The Change in Renin Angiotensin Aldosterone System (RAAS) Markers and Neurohormonal Activation After an 8 week Treatment with Febuxostat

Description

RAAS and neurohormonal markers will be measured in euglycemic and hyperglycemic conditions before and after an 8 week treatment with febuxostat.

Time Frame

Before and after an 8 week treatment with febuxostat.

Title

The Change in Levels of Vasodilators in Plasma After an 8 week Treatment with Febuxostat

Description

Levels of vasodilators will be measured in plasma in euglycemic and hyperglycemic conditions before and after an 8 week treatment with febuxostat.

Time Frame

Before and after an 8 week treatment with febuxostat.

Title

The Change in Blood Pressure After an 8 week Treatment with Febuxostat

Description

Time Frame

Before and after an 8 week treatment with febuxostat.

Title

The Change in Flow Mediated Dilation After an 8 week Treatment with Febuxostat

Description

Flow Mediated Dilation will be measured in euglycemic and hyperglycemic conditions before and after an 8 week treatment with febuxostat.

Time Frame

Before and after an 8 week treatment with febuxostat.

Title

The Change in Arterial Stiffness After an 8 week Treatment with Febuxostat

Description

Arterial Stiffness will be measured in euglycemic and hyperglycemic conditions before and after an 8 week treatment with febuxostat.

Time Frame

Before and after an 8 week treatment with febuxostat.

Title

The Change in Skin Biopsy Measures of Neurohormonal Activation After an 8 week Treatment with Febuxostat

Description

Skin biopsy neurohormonal activation biomarkers will be measured in euglycemic conditions before and after an 8 week treatment with febuxostat.

Time Frame

Before and after an 8 week treatment with febuxostat.

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

40 Years

Accepts Healthy Volunteers

Eligibility Criteria

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

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

David ZI Cherney, MD, PhD

Organizational Affiliation

University Health Network, Toronto

Official's Role

Principal Investigator

Facility Information:

Facility Name

Renal Physiology Laboratory, University Health Network

City

Toronto

State/Province

Ontario

ZIP/Postal Code

M5G 2N2

Country

Canada

12. IPD Sharing Statement

Citations:

PubMed Identifier

28408434

Citation

Lytvyn Y, Har R, Locke A, Lai V, Fong D, Advani A, Perkins BA, Cherney DZI. Renal and Vascular Effects of Uric Acid Lowering in Normouricemic Patients With Uncomplicated Type 1 Diabetes. Diabetes. 2017 Jul;66(7):1939-1949. doi: 10.2337/db17-0168. Epub 2017 Apr 13.

Results Reference

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The Effect of Uric Acid Lowering in Type 1 Diabetes

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