Empaglifozin in Early Diabetic Kidney Disease

NCT03173963 | Withdrawn Phase 3

• 2 other identifiers: 99991710317-DK-N103
• Study Type: interventional
• Target: N/A
• Locations: 1 country
• Sites: 1

Brief Summary

Background: Diabetes is common among American Indian people and diabetic kidney disease is a common complication. Kidney disease caused by diabetes can lead to the need for kidney replacement, by dialysis or kidney transplant, and is also associated with higher risk of early death. A new diabetes medicine called empagliflozin may slow kidney disease from type 2 diabetes. Researchers want to learn if it protects the kidneys when used in very early stages of diabetic kidney disease. Objectives: To see if empaglifozin delays kidney disease development. Eligibility: Adults 18-64 years old who are at least half American Indian and have had type 2 diabetes at least 5 years Design: Participants will be screened with health questions, blood pressure, and blood and urine tests. Participants will have:

• Medical history
• Physical exam
• Blood, urine, and stool samples taken
• Scan of the kidneys and liver. Participants will lie on a table that slides into an MRI machine. They will hold their breath for up to 20 seconds and the MRI machine will take images of their kidneys and liver. They will then repeat this with a small device that vibrates on their side.
• Kidney tests. A needle will be placed in a vein in each arm for 4 hours. Blood pressure will be taken. Participants will drink several quarts of water and urinate every 20 minutes. Urine and blood samples will be collected. Two liquids will be injected into their veins to measure kidney function.
• Photos of the back of the eyes
• Kidney biopsy. Participants will have a scan and get drugs to make them sleepy. Up to four very small pieces of kidney will be removed by needle. After the biopsy participants will be monitored for at least 4 hours.
• Nerve tests Participants will take the study drug or placebo pill once a day. Participants will attend for tests every twelve weeks and have more extensive kidney function tests once a year. After 3 years, participants will have another kidney biopsy and then stop taking the study drug. They will have a final kidney function test 2 months later.

Conditions

Diabetic Kidney Disease; Diabetes Mellitus Type 2

Keywords

Sodium Glucose Co-Transporter 2 (SGLT2) Inhibitor; Kidney Biopsy; Morphometry; American Indians; Glomerular Filtration Rate

Outcome Measures

Primary Outcomes (1)

• Effect of empagliflozin on change in cortical interstitial fractional volume [Vv(Int/cortex) over the 3-year study period.

  Cortical interstitial fractional volume is a measure of the proportion of kidney cortex made up of interstitium. The measurement is made using light microscopy images of kidney tissue. It is positively associated with progression of diabetic kidney disease and is the glomerular measurement that changes most dramatically over time in diabetic kidney disease. We will compare change in cortical interstitial fractional volume from baseline to 3-year biopsy in the group randomized to Empagliflozin and the group randomized to placebo.

  3 years

Secondary Outcomes (3)

• Effect of empagliflozin on changes in total interstitium per cortex per kidney, mesangial fractional volume, glomerular basement membrane width, glomerular filtration surface density, and total filtration surface per glomerulus.

  3 years

• Effect of empagliflozin on changes in podocyte numerical density, podocyte number per glomerulus, podocyte foot process width, percentage podocyte detachment, and percentage glomerular endothelial cell fenestration.

  3 years

• Effect of empagliflozin on development or progression of diabetic retinopathy determined by changes from baseline to 3 years of at least 2 Early Treatment of Diabetic Retinopathy Study levels in grading of standardized retinal photographs.

  3 years

Study Arms (2)

Drug

ACTIVE COMPARATOR

Empagliflozin 10mg once a day

Drug: Empagliflozin

Placebo

PLACEBO COMPARATOR

1 placebo tablet a day

Other: Placebo

Interventions

Empagliflozin DRUG

10 mg tablet of empagliflozin daily in addition to best clinical practice for management of diabetes.

Drug

Placebo OTHER

1placebo tablet per day

Placebo

Eligibility Criteria

• Age: 18 Years - 64 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64)

You may qualify if:

• To be eligible for participation in the study, participants must meet the following criteria:
• American Indian heritage participants must be at least half American Indian (i.e. 2 out of 4 grand-parents)
• Aged 18-64 years. The lower age limit was set so renal function test results would not reflect changes associated with growth and the upper limit was set to avoid the bladder emptying problems often encountered in older people, since complete bladder emptying is crucial to the accuracy of the renal function measurements done in this study.
• Diagnosis of type 2 diabetes for greater than or equal to 5 years.
• Estimated GFR \>60/ml/min as determined from the CKD-EPI equation using serum creatinine (Levey et al., 2009) or serum creatinine concentration \<1.4 mg/dl in women and \<1.5 mg/dl in men.
• Serum potassium concentration less than or equal to 5.5 mEq/L.
• A screening urinary albumin-to-creatinine ratio \<300 mg/g.
• Willingness to participate after receiving a thorough explanation of the study.
• Participants receiving a RAS blocker must have been receiving the drug for at least 3 months prior to the study baseline examination.

You may not qualify if:

• Volunteers will be excluded prior to enrollment for the following reasons:
• Clinically significant disorders of the liver \[cirrhosis, portal hypertension, hepatitis, increased bilirubin (greater than or equal to 1.5 mg/dl), cardiovascular disease (angina pectoris, history of myocardial infarction, heart failure, cerebrovascular disease, peripheral vascular disease, pulmonary diseases (asthma and restrictive or obstructive lung disease requiring therapy), renal-urinary disorders (calculi, urinary tract obstruction, glomerulonephritis, chronic infection), gastrointestinal disorders (nausea, vomiting, diarrhea or anorexia sufficient to cause weight loss or wasting), or hematocrit levels less than or equal to 30 percent or \>55 percent in women or greater than or equal to 35 percent or \>60 percent in men.
• Prior treatment with SGLT2 inhibitors.
• Renovascular or malignant hypertension; uncontrolled hypertension (systolic blood pressure greater than or equal to 160 or diastolic greater than or equal to 95 mm Hg) despite treatment with three antihypertensive drugs.
• Hematuria of unknown etiology. Prior to entry into the study, any participant with hematuria should be evaluated, the etiology established and documented, and treatment rendered as appropriate.
• Chronic debilitating disorders with or without treatment (e.g., systemic lupus erythematosus (SLE), cancer, amyloidosis, and chronic infection) that would interfere with the assessment of kidney function or that might reduce the chances of survival for a sufficient length of time to evaluate the efficacy of treatment.
• Currently receiving a drug regimen that includes: steroids, immunosuppressants, or investigational new drugs.
• Pregnancy. Boerhinger Ingelheim, the manufacturer of empagliflozin, do not recommend its use during the second or third trimester of pregnancy. Moreover, we do not wish to expose pregnant women to conscious sedation that is used during the kidney biopsies or to the intravenous filtration markers iothalamate and para-aminohippurate needed for the renal clearance studies. Women of childbearing potential must have a negative pregnancy test prior to entry and every 3 months during the study, and agree to using an effective form of contraception throughout the study, such as the oral contraceptive pill or an intrauterine device. Women who are planning a pregnancy in the next three years will be excluded.
• Symptoms of inability to empty the bladder. The urinary clearance method is only accurate if complete bladder emptying is possible.
• Hypersensitivity to empagliflozin or iodine.
• Bleeding disorders or requirements for anticoagulation or platelet inhibitors which cannot be safely interrupted, since kidney biopsies cannot be performed safely in these individuals.
• Massive obesity with body mass index greater than or equal to 45 kg/m(2). Kidney biopsies are more difficult and present greater hazards to people with massive obesity.
• Allergy to iodine-containing contrast material.
• Non-diabetic kidney disease based on clinical history or kidney biopsy examination.
• History of severe recurrent kidney infections.

Sponsors & Collaborators

• National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK): lead

Study Sites (1)

NIDDK, Phoenix

Phoenix, Arizona, 85014, United States

Location

Related Publications (3)

• 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.

  PMID: 27299675 BACKGROUND

• Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E, Hantel S, Mattheus M, Devins T, Johansen OE, Woerle HJ, Broedl UC, Inzucchi SE; EMPA-REG OUTCOME Investigators. Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes. N Engl J Med. 2015 Nov 26;373(22):2117-28. doi: 10.1056/NEJMoa1504720. Epub 2015 Sep 17.

  PMID: 26378978 BACKGROUND

• Cordonnier DJ, Pinel N, Barro C, Maynard M, Zaoui P, Halimi S, Hurault de Ligny B, Reznic Y, Simon D, Bilous RW. Expansion of cortical interstitium is limited by converting enzyme inhibition in type 2 diabetic patients with glomerulosclerosis. The Diabiopsies Group. J Am Soc Nephrol. 1999 Jun;10(6):1253-63. doi: 10.1681/ASN.V1061253.

  PMID: 10361863 BACKGROUND

MeSH Terms

Conditions

Diabetic Nephropathies; Diabetes Mellitus, Type 2

Interventions

empagliflozin

Condition Hierarchy (Ancestors)

Kidney Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Diabetes Complications; Diabetes Mellitus; Endocrine System Diseases; Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases

Study Officials

• Helen C Looker

  National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 27, 2017
• First Posted: June 2, 2017
• Study Start: May 27, 2017
• Primary Completion: February 21, 2020
• Study Completion: February 21, 2020
• Last Updated: February 25, 2020

Record last verified: 2020-02

Locations

US (1)