Type 1 Diabetes MellitusPhase 4NCT02344602
The Effect of Uric Acid Lowering in Type 1 Diabetes
A Phase 4 study testing Febuxostat in people with Type 1 Diabetes Mellitus, run by University Health Network, Toronto at 1 site in Canada.
Trial 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… Read more about this study
- Who is it for?
- Ages 18 to 40 yearsHealthy volunteers can take part
- Conditions the study is for
- Type 1 Diabetes Mellitus
- What is being tested?
- Febuxostat
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 73 participants
- Where
- 1 siteCanada
- Study dates
- 18 Dec 2012to 22 Sep 2015
- Phase
- Phase 4
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 40 years
- All sexes
- Healthy volunteers accepted
- Adult
Who may be able to join
- 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)
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- 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
Who cannot join
- 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
Show all 20Show fewer
- 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
Trial locations and contacts
1 site in 1 country.
Canada1 site
Renal Physiology Laboratory, University Health Network
Toronto, Ontario, M5G 2N2
About this study
Official title: 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.
Read more
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.
Read the 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.
- Conditions
- Type 1 Diabetes Mellitus
- Being tested
- Febuxostat
- 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
- Medical subject headings
- Diabetes Mellitus, Type 1, Diabetic Nephropathies, Diabetes Mellitus, Diabetes Complications, Kidney Diseases, Vascular Diseases, Cardiovascular Diseases, Hyperglycemia
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
FebuxostatDrug
Also called Trade name Uloric®
Oral tablet, 80mg, OD, 8 weeks
| Study group | Role | What they receive |
|---|---|---|
| Febuxostat (trade name Uloric®) | Experimental | Oral tablet, 80mg, OD, 8 weeks Receives: Drug: Febuxostat |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: 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.
Measured: 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
RAAS and neurohormonal markers will be measured in euglycemic and hyperglycemic conditions before and after an 8 week treatment with febuxostat.
Measured: 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.
Measured: 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.
Measured: Before and after an 8 week treatment with febuxostat.
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.
Measured: 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.
Measured: 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.
Measured: Before and after an 8 week treatment with febuxostat.
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted26 Jan 2015 (estimated)
- Study start18 Dec 2012
- Primary completion22 Sep 2015
- Study completion22 Sep 2015
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Type 1 Diabetes MellitusStudies of the same condition, open and under way.
- More trials run by University Health Network, TorontoThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 4
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 73 participants (actual)
Sponsor and investigators
- Lead sponsor
- University Health Network, Toronto
- Sponsor type
- University, hospital or other
- Collaborators
- Canadian Institutes of Health Research (CIHR), Toronto General Hospital, University of Toronto
- Responsible party
- Principal investigator, David Z.I. Cherney, University Health Network, Toronto
- Investigators
- David ZI Cherney, MD, PhD, Principal investigator, University Health Network, Toronto
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02344602
- Sponsor's protocol ID
- 12-5427-A
- Status last verified
- Jan 2018
- First submitted
- 9 Jan 2015
- Last updated
- 16 Jan 2018
- Results posted
- No
- Data monitoring committee
- No
Publications
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.
PubMed 28408434
Study at a glance
From the registry record, last updated by the sponsor on 16 Jan 2018. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Deep Phenotyping Approach to Assess the Effect of Uric Acid Lowering in Patients With Uncomplicated Type 1 Diabetes Mellitus
- ClinicalTrials.gov ID
- NCT02344602
- Acronym / sponsor ID
- 12-5427-A
- Conditions
- Type 1 Diabetes Mellitus
- Keywords
- Diabetic Nephropathy, Diabetes Mellitus, Diabetes Complications, Uric Acid, Febuxostat, Uloric, Glomerular Filtration Rate, Kidney Disease
- Phase
- Phase 4
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 73 participants (actual)
- Lead sponsor
- University Health Network, TorontoUniversity, hospital or other
- Collaborators
- Canadian Institutes of Health Research (CIHR), Toronto General Hospital, University of Toronto
- Study start
- 18 Dec 2012 (actual)
- Primary completion
- 22 Sep 2015 (actual)
- Study completion
- 22 Sep 2015 (actual)
- First posted
- 26 Jan 2015 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Febuxostat (trade name Uloric®) | Experimental | Drug: FebuxostatOral tablet, 80mg, OD, 8 weeks |
Who may qualify
- Ages
- 18 to 40 years
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Adult
Key inclusion criteria (12 listed)
- 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
Key exclusion criteria (20 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| FebuxostatAlso: Trade name Uloric®Oral tablet, 80mg, OD, 8 weeks | Drug | Febuxostat (trade name Uloric®) |
Primary outcome
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.
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.
6 secondary outcomes
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.
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.
The Change in Blood Pressure After an 8 week Treatment with Febuxostat
Time frame: 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.
The Change in Arterial Stiffness After an 8 week Treatment with Febuxostat
Time frame: 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.
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 16 Jan 2018.
- Derived from this study: PubMed 28408434Lytvyn 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.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
David ZI Cherney, MD, PhD principal investigator
University Health Network, Toronto
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 4 study testing Febuxostat in people with Type 1 Diabetes Mellitus, run by University Health Network, Toronto at 1 site in Canada.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 12 inclusion and 20 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 16 Jan 2018. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Canada. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
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.). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT02344602, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 16 Jan 2018.