- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT02252081
Metformin in Kidney Disease
Dysmetabolism of Chronic Kidney Disease and Vascular Health
Chronic kidney disease (CKD) is a major global health problem associated with substantial costs and resource utilization. Currently, CKD affects more than 500 million people worldwide. Patients with CKD have unacceptably high mortality rates due to cardiovascular (CV) causes, which are not entirely explained by traditional CV risk factors. The mortality rates in advanced CKD are six times higher compared to the Medicare population, with CVD accounting for the overwhelming majority of deaths. Insulin resistance (IR) is common in CKD patients and may represent a central link between CKD and the increased CVD risk observed in this population. Insulin resistance may increase CV risk by impairing and worsening endothelial function, increasing reactive oxygen species, and exacerbating systemic inflammation-hence, insulin resistance is considered a "non-traditional CV risk factor" in CKD.
Obesity (defined by a body mass index [BMI] of at least 30 kg/m2) is a major public health problem-the upward trend in obesity prevalence across regions and continents is a worldwide concern. Obesity increases the risk for cardiovascular disease and death. In the general population, obesity hastens death by 9.4 years. Obesity is an independent risk factor for CKD. Besides its contribution to the development of diabetes and hypertension, increased fat mass may also have a direct impact on kidney function.
In spite of the increasing prevalence of both obesity and CKD, the impact of obesity in the CKD population is not known, especially in terms of the exaggerated metabolic disturbances associated with their coexistence. It is highly likely that these two conditions have profound interactions that exaggerate the severity of the metabolic derangements when they coexist, particularly in regards to adipokine dysregulation, the risk of "insulin resistance", and downstream effects on vascular health. The current proposal will attempt to characterize the relative and combined impact of both obesity and CKD on metabolic disturbances, which may aid in risk stratification and identifying specific targets for intervention.
The ultimate goal of this proposal is to understand the relative and combined impact of obesity and CKD on the generation and maintenance of insulin resistance and their impact on cardiovascular health.
Specific Aim 2: To study the effects of metformin, an AMPK activator, on metabolic disturbances associated with obesity and moderate CKD.
S.A.2.a: To test if metformin will improve LAR in obese patients with moderate CKD compared to placebo.
S.A.2.b: To test if metformin will improve markers of systemic inflammation, oxidative stress, endothelial dysfunction in obese patients with moderate CKD compared to placebo.
S.A.2.c: To test if metformin will improve atherosclerosis markers and reduce clinical CVD events in obese patients with moderate CKD compared to placebo.
Hypothesis: The investigators hypothesize that the administration of metformin in obese CKD patients will significantly improve the adipokine profiles-particularly through a reduction in LAR. Additionally, that it will improve systemic inflammation, oxidative stress and endothelial function, which may or may not be mediated by changes in adipokines. Finally, the investigators hypothesize that improvements in these markers of vascular health will translate into reduced arterial stiffness and less clinical CV events
Study Overview
Status
Intervention / Treatment
Study Type
Enrollment (Actual)
Phase
- Phase 2
Contacts and Locations
Study Locations
-
-
Tennessee
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Nashville, Tennessee, United States, 37212-2637
- Tennessee Valley Healthcare System Nashville Campus, Nashville, TN
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-
Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Description
Inclusion Criteria:
- Age 18 years old;
- Ability to give informed consent;
- Life expectancy greater than 6 months;
- Estimated GFR 30-59 ml/min/1.73m^2;
- Overweight (BMI >=25 to < 30 kg/m^2) or obese (BMI >=30 kg/m^2); or normal (BMI >=18.5 to <25 kg/m^2) if pre-diabetic or insulin resistant.
Exclusion Criteria:
- Pregnancy or breast feeding;
- Presence or history of Diabetes Mellitus type I or II
- History of metformin use or any insulin sensitizer or any drug for the treatment of metabolic syndrome over the last one year;
- Any acute kidney injury episode in the last 4 months due to the risk of recurrent AKI;
- Proteinuria of > 5 g in 24 hours determined by a 24 hour urine collection or PCR > 4.5;
- Uncontrolled hypertension with systolic blood pressure 160 mmHg and diastolic blood pressure 100 mmHg;
- Patients with new changes to their antihypertensive regimen over the last 1 month;
- Severe, unstable, or active inflammatory disease; active infection including seropositive HIV, Hepatitis B or C; active connective tissue disorder; or moderate to severe liver disease;
- Decompensated heart failure;
- Recent hospitalization or surgical procedure within 1 month prior to the study for any cause;
- Current active malignancy or cancer history in the prior 5 years (excluding squamous cell and basal cell skin cancers);
- Known intolerance to the study drug;
- Patient receiving oral or injected steroids
- Use of any investigational product or device within 30 days prior to screening, or requirement for any investigational agent prior to completion of all scheduled study assessments;
Study Plan
How is the study designed?
Design Details
- Primary Purpose: TREATMENT
- Allocation: RANDOMIZED
- Interventional Model: PARALLEL
- Masking: QUADRUPLE
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
ACTIVE_COMPARATOR: metformin
500 to 1500 mg orally per day for 16 weeks if eGFR > 45 ml/min; 500 to 1000 mg orally per day for 16 weeks if eGFR =< 45 ml/min
|
500 to 1500 mg orally per day for 16 weeks if eGFR > 45 ml/min; 500 to 1000 mg orally per day for 16 weeks if eGFR =< 45 ml/min
|
PLACEBO_COMPARATOR: Placebo
placebo pill(s) orally per day for 16 weeks
|
placebo pill(s) orally per day for 16 weeks
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Change is Leptin to Adiponectin Ratio (LAR)
Time Frame: 16 weeks after start of treatment
|
Change in leptin to adiponectin ratio (LAR) after 4 months of metformin vs. placebo will be assessed as a biomarker of insulin resistance in CKD
|
16 weeks after start of treatment
|
Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Change in Flow-mediated Dilation (FMD)
Time Frame: 16 weeks after the start of treatment
|
Change in FMD after 4 months of treatment with metformin will be compared to change in the placebo group.
|
16 weeks after the start of treatment
|
Aortic Pulse-wave Velocity (aPWV)
Time Frame: 16 weeks after starting treatment
|
is a measurement of stiffening of the large elastic arteries and atherosclerosis.
It is a subclinical marker of cardiovascular disease
|
16 weeks after starting treatment
|
Other Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Estimated Glomerular Filtration Rate (eGFR)
Time Frame: baseline and 16 weeks after starting treatment
|
eGFR is a measurement of kidney function, this was a descriptive measurement
|
baseline and 16 weeks after starting treatment
|
Collaborators and Investigators
Study record dates
Study Major Dates
Study Start (ACTUAL)
Primary Completion (ACTUAL)
Study Completion (ACTUAL)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (ESTIMATE)
Study Record Updates
Last Update Posted (ACTUAL)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Additional Relevant MeSH Terms
Other Study ID Numbers
- ENDA-014-13F
- 1I01CX000982-01A1 (NIH)
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
IPD Plan Description
No we do not plan to make individual level data available.
This is a pilot mechanistic study.
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Studies a U.S. FDA-regulated device product
product manufactured in and exported from the U.S.
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.
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