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出境医 / 临床实验 / Metabolic Effects of the SGLT-2 Inhibitor Empagliflozin in Patients With Diabetic Nephropathy (MEDiaN) ((MEDiaN))

Metabolic Effects of the SGLT-2 Inhibitor Empagliflozin in Patients With Diabetic Nephropathy (MEDiaN) ((MEDiaN))

Study Description
Brief Summary:

The MEDiaN study aims to examine the state of fuel metabolism in participants with diabetic nephropathy (DN) before and after the use of the sodium-glucose transport protein 2 inhibitor (SGLT-2i) empagliflozin. The goals of the MEDiaN study are to better understand the contribution of fuel metabolism to the development of DN, and to determine if changes to fuel metabolism can have a positive impact on this disease.

The MEDiaN study is a single-center single-arm open-label intervention study to examine the effects of empagliflozin 10mg daily taken for 30 days on fuel oxidation patterns in participants with type 2 diabetes and DN.


Condition or disease Intervention/treatment Phase
Diabetic Nephropathies Drug: Empagliflozin 10 MG Phase 3

Detailed Description:

Diabetic nephropathy (DN) is a common cause of end-stage renal disease. MEDiaN study investigators hypothesize that dysregulated mitochondrial fuel oxidation is a major driver of diabetic nephropathy. The sodium-glucose transport protein 2 inhibitor (SGLT-2i) empagliflozin has been shown to slow the progression of DN in patients with diabetes.

The MEDiaN study aims to examine the state of fuel metabolism in participants with DN before and after the use of the SGLT-2i empagliflozin. The goals of the MEDiaN study are to better understand the contribution of fuel metabolism to the development of DN, and to determine if changes to fuel metabolism can have a positive impact on this disease.

The MEDiaN study is a single-center single-arm open-label intervention study to examine the effects of empagliflozin 10mg daily taken for 30 days on fuel oxidation patterns in participants with type 2 diabetes and DN.

The MEDiaN study plans to recruit 40 participants aged 21 to 100 years of age with type 2 diabetes mellitus and diabetic nephropathy. Participants will receive treatment with oral empagliflozin 10mg daily for 30 days. The state of fuel metabolism will be examined through metabolomics analysis of blood and urine samples before and after empagliflozin 10mg daily taken for 30 days.

Study Design
Layout table for study information
Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 2 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Intervention Model Description: Single-arm open-label intervention study
Masking: None (Open Label)
Primary Purpose: Basic Science
Official Title: Metabolic Effects of the SGLT-2 Inhibitor Empagliflozin in Patients With Diabetic Nephropathy (MEDiaN)
Actual Study Start Date : January 9, 2020
Actual Primary Completion Date : August 1, 2020
Actual Study Completion Date : August 1, 2020
Arms and Interventions
Arm Intervention/treatment
Experimental: Empagliflozin-treated
Oral empagliflozin tablets 10mg daily, taken for 30 days.
 Drug: Empagliflozin 10 MG
Oral empagliflozin 10mg daily for 30 days
Other Name: Jardiance
Outcome Measures
Primary Outcome Measures :
  1. Change in lipid metabolome signature [ Time Frame: Baseline and after 30 days of treatment with empagliflozin 10mg daily ]
    Change in lipid metabolome signature following 30 days of empagliflozin treatment

  2. Change in ketone signature [ Time Frame: Baseline and after 30 days of treatment with empagliflozin 10mg daily ]
    Change in ketone signature following 30 days of empagliflozin treatment

  3. Change in amino acid metabolome signature [ Time Frame: Baseline and after 30 days of treatment with empagliflozin 10mg daily ]
    Change in amino acid metabolome signature following 30 days of empagliflozin treatment


Eligibility Criteria
Layout table for eligibility information
Ages Eligible for Study:   21 Years to 100 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion criteria:

  1. Man or woman between 21 and 100 years of age

  2. Type 2 diabetes mellitus as defined by:

    • Fasting plasma glucose ≥7.0mmol/l, or
    • Symptoms of hyperglycemia with casual plasma glucose ≥11.1 mmol/L, or
    • 2-hour plasma glucose ≥11.1 mmol/l after a 75-gram oral glucose load, or
    • Known type 2 diabetes mellitus diagnosed by a medical practitioner

  3. Two or more measurements indicating increased urine protein excretion within 1-year

    Increased urine protein excretion is defined as:

    • Urine microalbumin/creatinine ratio (ACR) > 3.3 mg/mmol creatinine or
    • Urine total protein/creatinine ratio (PCR) > 0.2 g/urine creatinine
  4. Known diabetes duration > 3 months
  5. HbA1c ≤9% (within 3 months prior to enrolment)
  6. Not currently treated with an SGLT-2 inhibitor, and have not received SGLT-2 inhibitor therapy within the last 10 weeks.

  7. Stable diabetes therapy for at least 3months as defined as:

    • No increase in dose of diabetes medications by more than two-fold or
    • No new agents added within the previous 3 months
  8. Stable doses of angiotensin converting enzyme (ACE) inhibitors or angiotensin AT(1)-receptor blockers (ARBs) for at least 3 months.
  9. Capable of providing informed consent

Exclusion Criteria:

  1. Type 1 diabetes mellitus
  2. Ketosis-prone diabetes
  3. Previous diabetic ketoacidosis
  4. History of Fournier's gangrene or skin and soft tissue infections of the perineum
  5. Recurrent or severe urinary tract or genital mycotic infections, or history of genitourinary infection within 2 weeks prior to informed consent
  6. Significant renal impairment (estimated Glomerular Filtration Rate < 45 ml/min/1.73m2**)
  7. Dialysis or kidney transplant
  8. Renal artery stenosis
  9. Alanine aminotransferase or aspartate aminotransferase above 3x upper limit of normal
  10. Significant change in weight (≥10% in the preceding 6 months)
  11. Treatment with anti-obesity drugs
  12. Previous bariatric surgery or other gastrointestinal surgeries that induce chronic malabsorption
  13. Treatment with systemic glucocorticoids
  14. Blood dyscrasias or clinically significant anaemia (Haemoglobin < 10 g/L)
  15. Medical condition likely to limit survival to less than 3 years
  16. Uncontrolled thyrotoxicosis, untreated hypothyroidism
  17. Any ongoing acute medical illnesses
  18. Hospitalization within 1 month prior to enrolment
  19. Nursing mothers
  20. Pregnancy, currently trying to become pregnant, or of child-bearing potential and not practicing an acceptable method of birth control or do not plan to continue using this method throughout the study
  21. Excessive alcohol intake (> 1 unit per day for women and > 2 units per day for men)
  22. History of drug abuse
  23. Pancreatic insulin deficiency from any cause (history of pancreatitis, pancreatic surgery)
  24. Known intolerance or allergic reactions to empagliflozin or other SGLT-2 inhibitors
  25. Current participation in another clinical trial, or ingestion of investigational drug in another trial within 30 days prior to enrolment.
  26. Presence of any non-DN renal glomerular disease (e.g. IgA nephropathy, lupus nephritis, membranous glomerulonephritis, focal segmental glomerular sclerosis)
  27. Any previous organ transplantation
  28. Any factors likely to limit adherence to interventions (e.g. dementia; alcohol or substance abuse; history of unreliability in medication taking or appointment keeping; significant concerns about participation in the study from spouse, significant other or family members)
  29. Failure to obtain informed consent from participant
  30. Presence of postural hypotension or clinically significant dehydration (reduced skin turgor, dry oral mucosa, hypotension)
Contacts and Locations

Locations
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Singapore
Singapore General Hospital
Singapore, Singapore, 169608
Sponsors and Collaborators
Singapore General Hospital
Duke-NUS Graduate Medical School
Investigators
Layout table for investigator information
Principal Investigator: Yun Rui Amanda Lam, MBBS MRCP Singapore General Hospital
Tracking Information
First Submitted Date  ICMJE April 20, 2019
First Posted Date  ICMJE May 1, 2019
Last Update Posted Date December 17, 2020
Actual Study Start Date  ICMJE January 9, 2020
Actual Primary Completion Date August 1, 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: April 28, 2019)
  • Change in lipid metabolome signature [ Time Frame: Baseline and after 30 days of treatment with empagliflozin 10mg daily ]
    Change in lipid metabolome signature following 30 days of empagliflozin treatment
  • Change in ketone signature [ Time Frame: Baseline and after 30 days of treatment with empagliflozin 10mg daily ]
    Change in ketone signature following 30 days of empagliflozin treatment
  • Change in amino acid metabolome signature [ Time Frame: Baseline and after 30 days of treatment with empagliflozin 10mg daily ]
    Change in amino acid metabolome signature following 30 days of empagliflozin treatment
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE Not Provided
Original Secondary Outcome Measures  ICMJE Not Provided
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Metabolic Effects of the SGLT-2 Inhibitor Empagliflozin in Patients With Diabetic Nephropathy (MEDiaN)
Official Title  ICMJE Metabolic Effects of the SGLT-2 Inhibitor Empagliflozin in Patients With Diabetic Nephropathy (MEDiaN)
Brief Summary

The MEDiaN study aims to examine the state of fuel metabolism in participants with diabetic nephropathy (DN) before and after the use of the sodium-glucose transport protein 2 inhibitor (SGLT-2i) empagliflozin. The goals of the MEDiaN study are to better understand the contribution of fuel metabolism to the development of DN, and to determine if changes to fuel metabolism can have a positive impact on this disease.

The MEDiaN study is a single-center single-arm open-label intervention study to examine the effects of empagliflozin 10mg daily taken for 30 days on fuel oxidation patterns in participants with type 2 diabetes and DN.
Detailed Description

Diabetic nephropathy (DN) is a common cause of end-stage renal disease. MEDiaN study investigators hypothesize that dysregulated mitochondrial fuel oxidation is a major driver of diabetic nephropathy. The sodium-glucose transport protein 2 inhibitor (SGLT-2i) empagliflozin has been shown to slow the progression of DN in patients with diabetes.

The MEDiaN study aims to examine the state of fuel metabolism in participants with DN before and after the use of the SGLT-2i empagliflozin. The goals of the MEDiaN study are to better understand the contribution of fuel metabolism to the development of DN, and to determine if changes to fuel metabolism can have a positive impact on this disease.

The MEDiaN study is a single-center single-arm open-label intervention study to examine the effects of empagliflozin 10mg daily taken for 30 days on fuel oxidation patterns in participants with type 2 diabetes and DN.

The MEDiaN study plans to recruit 40 participants aged 21 to 100 years of age with type 2 diabetes mellitus and diabetic nephropathy. Participants will receive treatment with oral empagliflozin 10mg daily for 30 days. The state of fuel metabolism will be examined through metabolomics analysis of blood and urine samples before and after empagliflozin 10mg daily taken for 30 days.
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Intervention Model Description:
Single-arm open-label intervention study
Masking: None (Open Label)
Primary Purpose: Basic Science
Condition  ICMJE Diabetic Nephropathies
Intervention  ICMJE Drug: Empagliflozin 10 MG
Oral empagliflozin 10mg daily for 30 days
Other Name: Jardiance
Study Arms  ICMJE Experimental: Empagliflozin-treated
Oral empagliflozin tablets 10mg daily, taken for 30 days.
Intervention: Drug: Empagliflozin 10 MG
Publications *
  • Liu JJ, Ghosh S, Kovalik JP, Ching J, Choi HW, Tavintharan S, Ong CN, Sum CF, Summers SA, Tai ES, Lim SC. Profiling of Plasma Metabolites Suggests Altered Mitochondrial Fuel Usage and Remodeling of Sphingolipid Metabolism in Individuals With Type 2 Diabetes and Kidney Disease. Kidney Int Rep. 2016 Dec 16;2(3):470-480. doi: 10.1016/j.ekir.2016.12.003. eCollection 2017 May.
  • Sharma K, Karl B, Mathew AV, Gangoiti JA, Wassel CL, Saito R, Pu M, Sharma S, You YH, Wang L, Diamond-Stanic M, Lindenmeyer MT, Forsblom C, Wu W, Ix JH, Ideker T, Kopp JB, Nigam SK, Cohen CD, Groop PH, Barshop BA, Natarajan L, Nyhan WL, Naviaux RK. Metabolomics reveals signature of mitochondrial dysfunction in diabetic kidney disease. J Am Soc Nephrol. 2013 Nov;24(11):1901-12. doi: 10.1681/ASN.2013020126. Epub 2013 Oct 10.
  • Vasilakou D, Karagiannis T, Athanasiadou E, Mainou M, Liakos A, Bekiari E, Sarigianni M, Matthews DR, Tsapas A. Sodium-glucose cotransporter 2 inhibitors for type 2 diabetes: a systematic review and meta-analysis. Ann Intern Med. 2013 Aug 20;159(4):262-74. doi: 10.7326/0003-4819-159-4-201308200-00007. Review.
  • Wanner C, Inzucchi SE, Lachin JM, Fitchett D, von Eynatten M, Mattheus M, Johansen OE, Woerle HJ, Broedl UC, Zinman B; EMPA-REG OUTCOME Investigators. Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes. N Engl J Med. 2016 Jul 28;375(4):323-34. doi: 10.1056/NEJMoa1515920. Epub 2016 Jun 14.
  • Perrone-Filardi P, Avogaro A, Bonora E, Colivicchi F, Fioretto P, Maggioni AP, Sesti G, Ferrannini E. Mechanisms linking empagliflozin to cardiovascular and renal protection. Int J Cardiol. 2017 Aug 15;241:450-456. doi: 10.1016/j.ijcard.2017.03.089. Epub 2017 Mar 23. Review.
  • Mudaliar S, Alloju S, Henry RR. Can a Shift in Fuel Energetics Explain the Beneficial Cardiorenal Outcomes in the EMPA-REG OUTCOME Study? A Unifying Hypothesis. Diabetes Care. 2016 Jul;39(7):1115-22. doi: 10.2337/dc16-0542.
  • Ferrannini E, Muscelli E, Frascerra S, Baldi S, Mari A, Heise T, Broedl UC, Woerle HJ. Metabolic response to sodium-glucose cotransporter 2 inhibition in type 2 diabetic patients. J Clin Invest. 2014 Feb;124(2):499-508. doi: 10.1172/JCI72227. Epub 2014 Jan 27. Erratum in: J Clin Invest. 2014 Apr 1;124(4):1868.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Terminated
Actual Enrollment  ICMJE
 (submitted: December 13, 2020) 		2
Original Estimated Enrollment  ICMJE
 (submitted: April 28, 2019) 		40
Actual Study Completion Date  ICMJE August 1, 2020
Actual Primary Completion Date August 1, 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion criteria:

  1. Man or woman between 21 and 100 years of age

  2. Type 2 diabetes mellitus as defined by:

    • Fasting plasma glucose ≥7.0mmol/l, or
    • Symptoms of hyperglycemia with casual plasma glucose ≥11.1 mmol/L, or
    • 2-hour plasma glucose ≥11.1 mmol/l after a 75-gram oral glucose load, or
    • Known type 2 diabetes mellitus diagnosed by a medical practitioner

  3. Two or more measurements indicating increased urine protein excretion within 1-year

    Increased urine protein excretion is defined as:

    • Urine microalbumin/creatinine ratio (ACR) > 3.3 mg/mmol creatinine or
    • Urine total protein/creatinine ratio (PCR) > 0.2 g/urine creatinine
  4. Known diabetes duration > 3 months
  5. HbA1c ≤9% (within 3 months prior to enrolment)
  6. Not currently treated with an SGLT-2 inhibitor, and have not received SGLT-2 inhibitor therapy within the last 10 weeks.

  7. Stable diabetes therapy for at least 3months as defined as:

    • No increase in dose of diabetes medications by more than two-fold or
    • No new agents added within the previous 3 months
  8. Stable doses of angiotensin converting enzyme (ACE) inhibitors or angiotensin AT(1)-receptor blockers (ARBs) for at least 3 months.
  9. Capable of providing informed consent

Exclusion Criteria:

  1. Type 1 diabetes mellitus
  2. Ketosis-prone diabetes
  3. Previous diabetic ketoacidosis
  4. History of Fournier's gangrene or skin and soft tissue infections of the perineum
  5. Recurrent or severe urinary tract or genital mycotic infections, or history of genitourinary infection within 2 weeks prior to informed consent
  6. Significant renal impairment (estimated Glomerular Filtration Rate < 45 ml/min/1.73m2**)
  7. Dialysis or kidney transplant
  8. Renal artery stenosis
  9. Alanine aminotransferase or aspartate aminotransferase above 3x upper limit of normal
  10. Significant change in weight (≥10% in the preceding 6 months)
  11. Treatment with anti-obesity drugs
  12. Previous bariatric surgery or other gastrointestinal surgeries that induce chronic malabsorption
  13. Treatment with systemic glucocorticoids
  14. Blood dyscrasias or clinically significant anaemia (Haemoglobin < 10 g/L)
  15. Medical condition likely to limit survival to less than 3 years
  16. Uncontrolled thyrotoxicosis, untreated hypothyroidism
  17. Any ongoing acute medical illnesses
  18. Hospitalization within 1 month prior to enrolment
  19. Nursing mothers
  20. Pregnancy, currently trying to become pregnant, or of child-bearing potential and not practicing an acceptable method of birth control or do not plan to continue using this method throughout the study
  21. Excessive alcohol intake (> 1 unit per day for women and > 2 units per day for men)
  22. History of drug abuse
  23. Pancreatic insulin deficiency from any cause (history of pancreatitis, pancreatic surgery)
  24. Known intolerance or allergic reactions to empagliflozin or other SGLT-2 inhibitors
  25. Current participation in another clinical trial, or ingestion of investigational drug in another trial within 30 days prior to enrolment.
  26. Presence of any non-DN renal glomerular disease (e.g. IgA nephropathy, lupus nephritis, membranous glomerulonephritis, focal segmental glomerular sclerosis)
  27. Any previous organ transplantation
  28. Any factors likely to limit adherence to interventions (e.g. dementia; alcohol or substance abuse; history of unreliability in medication taking or appointment keeping; significant concerns about participation in the study from spouse, significant other or family members)
  29. Failure to obtain informed consent from participant
  30. Presence of postural hypotension or clinically significant dehydration (reduced skin turgor, dry oral mucosa, hypotension)
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 21 Years to 100 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Singapore
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03933956
Other Study ID Numbers  ICMJE MEDiaN2018
Duke-NUS-TIDR/2018/0010 ( Other Grant/Funding Number: Tanoto Initiative for Diabetes Research Award )
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Singapore General Hospital
Study Sponsor  ICMJE Singapore General Hospital
Collaborators  ICMJE Duke-NUS Graduate Medical School
Investigators  ICMJE
Principal Investigator: Yun Rui Amanda Lam, MBBS MRCP Singapore General Hospital
PRS Account Singapore General Hospital
Verification Date December 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP

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