The Effect of Uric Acid Lowering in Type 1 Diabetes

NCT02344602 | Completed Phase 4

• 1 other identifier: 12-5427-A
• Study Type: interventional
• Target: 73
• Locations: 1 country
• Sites: 1

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.

Conditions

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

Outcome Measures

Primary Outcomes (2)

• 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.

  Before and after an 8 week treatment with febuxostat.

• 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.

  Before and after an 8 week treatment with febuxostat

Secondary Outcomes (6)

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

  Before and after an 8 week treatment with febuxostat.

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

  Before and after an 8 week treatment with febuxostat.

• The Change in Flow Mediated Dilation 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

  Before and after an 8 week treatment with febuxostat.

Study Arms (1)

Febuxostat (trade name Uloric®)

EXPERIMENTAL

Oral tablet, 80mg, OD, 8 weeks

Drug: Febuxostat

Interventions

Febuxostat DRUG

Oral tablet, 80mg, OD, 8 weeks

Also known as: Trade name Uloric®

Febuxostat (trade name Uloric®)

Eligibility Criteria

• Age: 18 Years - 40 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• University Health Network, Toronto: lead
• Canadian Institutes of Health Research (CIHR): collaborator
• Toronto General Hospital: collaborator
• University of Toronto: collaborator

Study Sites (1)

Renal Physiology Laboratory, University Health Network

Toronto, Ontario, M5G 2N2, Canada

Location

Related Publications (1)

• 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.

  PMID: 28408434 DERIVED

MeSH Terms

Conditions

Diabetes Mellitus, Type 1; Diabetic Nephropathies; Diabetes Mellitus; Diabetes Complications; Kidney Diseases; Vascular Diseases; Cardiovascular Diseases; Hyperglycemia

Interventions

Febuxostat

Condition Hierarchy (Ancestors)

Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Endocrine System Diseases; Autoimmune Diseases; Immune System Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases

Intervention Hierarchy (Ancestors)

Thiazoles; Sulfur Compounds; Organic Chemicals; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds

Study Officials

• David ZI Cherney, MD, PhD

  University Health Network, Toronto

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: MD, PhD

Study Record Dates

• First Submitted: January 9, 2015
• First Posted: January 26, 2015
• Study Start: December 18, 2012
• Primary Completion: September 22, 2015
• Study Completion: September 22, 2015
• Last Updated: January 16, 2018

Record last verified: 2018-01

Locations

CA (1)