Chronic Kidney DiseasePhase 2NCT02252081
Metformin in Kidney Disease
A Phase 2 study testing metformin in people with Chronic Kidney Disease and Cardiovascular Disease, run by VA Office of Research and Development at 1 site in United States.
Trial summary
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. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Chronic Kidney Disease, Cardiovascular Disease, Metabolic Syndrome
- What is being tested?
- metformin
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 125 participants
- Where
- 1 siteUnited States
- Study dates
- 1 Oct 2014to 31 Dec 2019
- Phase
- Phase 2
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
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 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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.
Who cannot join
- 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;
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- 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;
Trial locations and contacts
1 site in 1 country.
United States1 site
Tennessee Valley Healthcare System Nashville Campus, Nashville, TN
Nashville, Tennessee, 37212-2637
About this study
Official title: 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.
Read more
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
- Being tested
- metformin, Placebo
- Keywords
- metformin, cardiovascular disease, Chronic Kidney Disease, Metabolic Syndrome
- Medical subject headings
- Renal Insufficiency, Chronic, Cardiovascular Diseases, Metabolic Syndrome
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
metforminDrug
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
PlaceboDrug
placebo pill(s) orally per day for 16 weeks
| Study group | Role | What they receive |
|---|---|---|
| metformin | Active comparator | 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 Receives: Drug: metformin |
| Placebo | Placebo comparator | placebo pill(s) orally per day for 16 weeks Receives: Drug: Placebo |
What is being measured
The primary outcome is the main question the study is designed to answer.
Change is Leptin to Adiponectin Ratio (LAR)
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
Measured: 16 weeks after start of treatment
Secondary outcomes (2)
Change in Flow-mediated Dilation (FMD)
Change in FMD after 4 months of treatment with metformin will be compared to change in the placebo group.
Measured: 16 weeks after the start of treatment
Aortic Pulse-wave Velocity (aPWV)
is a measurement of stiffening of the large elastic arteries and atherosclerosis. It is a subclinical marker of cardiovascular disease
Measured: 16 weeks after starting treatment
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted29 Sep 2014 (estimated)
- Study start1 Oct 2014
- Primary completion31 Dec 2019
- Study completion31 Dec 2019
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Chronic Kidney DiseaseStudies of the same condition, open and under way.
- More trials run by VA Office of Research and DevelopmentThe 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 2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 125 participants (actual)
Sponsor and investigators
- Lead sponsor
- VA Office of Research and Development
- Sponsor type
- US federal agency
- Responsible party
- Sponsor
- Investigators
- Adriana M Hung, MD MPH, Principal investigator, Tennessee Valley Healthcare System Nashville Campus, Nashville, TN
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02252081
- Sponsor's protocol ID
- ENDA-014-13F
- Other IDs
- 1I01CX000982-01A1
- Status last verified
- Oct 2021
- First submitted
- 25 Sep 2014
- Last updated
- 4 Nov 2021
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- No: No we do not plan to make individual level data available. This is a pilot mechanistic study.
Publications
El-Damanawi R, Stanley IK, Staatz C, Pascoe EM, Craig JC, Johnson DW, Mallett AJ, Hawley CM, Milanzi E, Hiemstra TF, Viecelli AK. Metformin for preventing the progression of chronic kidney disease. Cochrane Database Syst Rev. 2024 Jun 4;6(6):CD013414. doi: 10.1002/14651858.CD013414.pub2.
PubMed 38837240
Study at a glance
From the registry record, last updated by the sponsor on 4 Nov 2021. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Dysmetabolism of Chronic Kidney Disease and Vascular Health
- ClinicalTrials.gov ID
- NCT02252081
- Acronym / sponsor ID
- ENDA-014-13F
- Keywords
- metformin, cardiovascular disease, Chronic Kidney Disease, Metabolic Syndrome
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 125 participants (actual)
- Lead sponsor
- VA Office of Research and DevelopmentUS federal agency
- Study start
- 1 Oct 2014 (actual)
- Primary completion
- 31 Dec 2019 (actual)
- Study completion
- 31 Dec 2019 (actual)
- First posted
- 29 Sep 2014 (estimated)
- Results
- Posted 4 Nov 2021
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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 design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| metformin | Active comparator | Drug: metformin500 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 | Placebo comparator | Drug: Placeboplacebo pill(s) orally per day for 16 weeks |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (5 listed)
- 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.
Key exclusion criteria (14 listed)
- 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;
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 |
|---|---|---|
| metformin500 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 | Drug | metformin |
| Placeboplacebo pill(s) orally per day for 16 weeks | Drug | Placebo |
Primary outcome
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
2 secondary outcomes
Change in Flow-mediated Dilation (FMD)
Time frame: 16 weeks after the start of treatment
Aortic Pulse-wave Velocity (aPWV)
Time frame: 16 weeks after starting treatment
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 4 Nov 2021.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Derived from this study: PubMed 38837240El-Damanawi R, Stanley IK, Staatz C, Pascoe EM, Craig JC, Johnson DW, Mallett AJ, Hawley CM, Milanzi E, Hiemstra TF, Viecelli AK. Metformin for preventing the progression of chronic kidney disease. Cochrane Database Syst Rev. 2024 Jun 4;6(6):CD013414. doi: 10.1002/14651858.CD013414.pub2.
- Individual participant dataSharing planned: No. No we do not plan to make individual level data available. This is a pilot mechanistic study.
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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.
Adriana M Hung, MD MPH principal investigator
Tennessee Valley Healthcare System Nashville Campus, Nashville, TN
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing metformin in people with Chronic Kidney Disease and Cardiovascular Disease, run by VA Office of Research and Development at 1 site in United States.
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 5 inclusion and 14 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 4 Nov 2021. 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 United States. 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. Some participants in this study may receive a placebo. 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 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 4 Nov 2021). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
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?
Change is Leptin to Adiponectin Ratio (LAR) (time frame: 16 weeks after start of treatment). 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 NCT02252081, 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 4 Nov 2021.