Randomized Study Comparing Metabolic Surgery With Intensive Medical Therapy to Treat Diabetic Kidney Disease

Study Overview
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Brief Summary
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Proven therapy for DKD is primarily limited to RAAS blockers and SLGT2i. Weight reduction has the potential to become an additional and much needed treatment option. Of all the weight reduction strategies metabolic surgery is suited to be the most effective. Yet no study has of yet compared the effect of metabolic surgery against best medical treatment on the progression of DKD. This pilot trial is designed to be the first determine the efficacy of metabolic surgery in slowing progression of DKD as compared to best medical therapy. The study design will address all the major limitations previously documented, including the major dilemma of estimating versus measuring GFR. Of note, the study's design will allow its sample size to be adjusted upward using an adaptive design if necessary, to achieve statistical significance. It will also inform study design and sample size issues for all future studies in this field. The payoff of establishing metabolic surgery as a new and effective intervention to slow progression to ESRD would be great in terms of reducing patient suffering and societal costs. This will be an open-label, randomized trial involving sixty (60) patients with diabetic kidney disease (DKD) and obesity who will undergo Roux-en-Y gastric bypass (RYGB) in the intervention arm or receive best medical treatment (BMT) in the control arm. The aim of this prospective, open, randomized study is to evaluate the efficacy and safety of RYGB surgery versus best medical treatment on the progression of DKD in patients with type 2 diabetes and obesity.

Detailed Description
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This will be an open-label, randomized trial involving sixty (60) patients with DKD and obesity who will undergo RYGB (intervention arm) or receive BMT (control arm). Thirty (30) obese patients with DKD will undergo gastric bypass. Patients will also receive standard of care medical therapy for DKD (ACEI or ARB + SGLT2i) and T2DM (metformin, glitazones, incretin therapy - DPP4 inhibitor and GLP-1 analogs - and insulin, if necessary). Other comorbidities, such as hypertension and dyslipidemia, will be treated according to the latest recommendations of the ADA. The surgical procedure will consist of a laparoscopic surgery performed by an experienced surgeon (approximately 6000 bariatric surgeries), who is accredited as surgeon of excellence by the Brazilian Society of Bariatric and Metabolic Surgery and Surgical Review and Surgical Review Corporation program since 2009. Thirty (30) obese patients with DKD will undergo best medical treatment for DKD (ACEI or ARB + SGLT2i) and T2DM (metformin, glitazones, incretin therapy - DPP4 inhibitor and GLP-1 analogs - and insulin, if necessary). Other comorbidities, such as hypertension and dyslipidemia, will be treated according to the latest recommendations of the ADA. Regarding medication therapy: Metformin will be maintained in the postoperative period while fasting glycemia is above 100 mg/dL unless contraindicated. Anti-antihypertensive drugs and medications for dyslipidemia will be maintained in the postoperative period, unless contraindicated. Micronutrient supplementation (vitamins and mineral salts) will be prescribed to all patients undergoing metabolic surgery. Patients allocated to the control group will receive the same supplementation if necessary.

Official Title
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Open, Randomized, Unicenter Study Comparing Metabolic Surgery With Intensive Medical Therapy to Treat Diabetic Kidney Disease

Conditions
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Diabetes Mellitus, Type 2, Kidney Disease, Chronic, Kidney Injury

Intervention / Treatment
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* Procedure: Roux-en-Y gastric bypass
* Drug: Best medical treatment


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Female or male aged ≥30 and ≤70 years Diabetic kidney disease as defined by an estimated glomerular filtration rate (eGFR) (as estimated by CKD-EPI creatinine + cystatin C equation)72 between 45-59l/min/1.73m2 and macroalbuminuria (≥ 300 mg/g) in a 24 hr urine sample BMI ≥30-40 kg/m2 Fasting C-peptide over 1 ng/ml Negative glutamic acid decarboxylase autoantibodies test Patients having received accurate information about the surgery and requesting the procedure Patients having understood and accepted the need for long-term medical and surgical follow-up Effective method of contraception in women of child-bearing age Signed informed consent document Exclusion Criteria: Refusal to participate Autoimmune diabetes/type 1 diabetes Previous abdominal operations that would complicate a metabolic surgery or increase surgical risk Previous malabsorptive and restrictive surgeries Malabsorptive syndromes and inflammatory bowel disease Significant and/or severe hepatic disease that may complicate metabolic surgery Pregnancy or women of childbearing age without effective contraceptive Recent history of neoplasia (< 5 years), except for non-melanoma skin neoplasms History of liver cirrhosis, active chronic hepatitis, active hepatitis B or hepatitis C Major cardiovascular event in the last 6 months Current angina Pulmonary embolism or severe thrombophlebitis in the last 2 years Positive HIV serum testing Mental incapacity or severe mental illness Severe psychiatric disorders that would complicate follow-up after randomization Alcoholism or illicit drug use Uncontrolled coagulopathy Participation in other clinical trials in the past 30 days Inability to tolerate RAAS blockers and/or SGLT2i Iodine allergy History of acute kidney injury requiring renal replacement therapy Dialysis dependency Kidney transplantation Use of immunosuppressive drugs, chemotherapy and/or radiotherapy Any disorder which, in the opinion of the investigator, might jeopardize subject's safety or compliance with the protocol

Ages Eligible for Study
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Minimum Age: 30 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: This will be an open-label, randomized trial involving sixty (60) patients with DKD and obesity who will undergo RYGB (intervention arm) or receive BMT (control arm).
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: RYGB (intervention arm)<br>Thirty (30) obese patients with DKD will undergo gastric bypass. Patients will also receive standard of care medical therapy for DKD (ACEI or ARB + SGLT2i) and T2DM (metformin, glitazones, incretin therapy - DPP4 inhibitor and GLP-1 analogs - and insulin, if necessary). Other comorbidities, such as hypertension and dyslipidemia, will be treated according to the latest recommendations of the ADA. The surgical procedure will consist of a laparoscopic surgery performed by an experienced surgeon (approximately 6000 bariatric surgeries), who is accredited as surgeon of excellence by the Brazilian Society of Bariatric and Metabolic Surgery and Surgical Review and Surgical Review Corporation program since 2009. | Procedure: Roux-en-Y gastric bypass<br>* Pneumoperitoneum closed with Veress needle Identification of Treitz angle Measurement of biliary loop (50 cm) Bowel transection with linear stapler (white load) Measurement of the alimentary limb (100 cm) Laterolateral Entero-anastomoses (white load) Construction of gastric pouch distant about 3 cm from the esophageal-gastric junction with stomach section in the small curvature. Linear cutting anastomosis (gastrojejunostomy) from about 1 to 1.2 cm Anastomosis integrity evaluation by methylene blue test and/or perioperative air. Expected surgical time: 60 minutes<br>* Other names: RYGB;Drug: Best medical treatment<br>* Patients will also receive standard of care medical therapy for DKD (ACEI or ARB + SGLT2i) and T2DM (metformin, glitazones, incretin therapy - DPP4 inhibitor and GLP-1 analogs - and insulin, if necessary).<br>* Other names: BMT;|
| Active Comparator: BMT (control arm).<br>Thirty (30) obese patients with DKD will undergo best medical treatment for DKD (ACEI or ARB + SGLT2i) and T2DM (metformin, glitazones, incretin therapy - DPP4 inhibitor and GLP-1 analogs - and insulin, if necessary). Other comorbidities, such as hypertension and dyslipidemia, will be treated according to the latest recommendations of the ADA. | Drug: Best medical treatment<br>* Patients will also receive standard of care medical therapy for DKD (ACEI or ARB + SGLT2i) and T2DM (metformin, glitazones, incretin therapy - DPP4 inhibitor and GLP-1 analogs - and insulin, if necessary).<br>* Other names: BMT;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean differenceGlomerular filtration rate (GFR) | Mean difference in GFR between BMT and RYGB at the pre-specified time points of 12 and 36 months after randomization | At 12 and 36 months after randomization | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in twenty-four hour urinary albumin/protein excretion | Change in 24h urinary albumin/protein excretion | From baseline to 12 and 36 months | 
| Improvements in micro- or macroalbuminuria | Proportion of patients who achieve improvements in micro- or macroalbuminuria from baseline to 12 and 36 months | From baseline to 12 and 36 months | 
| Change in CKD stage and CKD prognostic risk | Change in CKD stage and CKD prognostic risk from baseline to month 12 and 36 | From baseline to 12 and 36 months | 
| Change in GFR, eGFR and 24 hr creatinine clearance | Change in GFR, eGFR and 24 hr creatinine clearance from baseline to months 12 and 36 | From baseline to 12 and 36 months | 
| Proportion of participants with ≥30%, ≥40%, and ≥50% reduction in GFR measurements | Proportion of participants with ≥30%, ≥40%, and ≥50% reduction in GFR measurements (GFR, eGFR and 24 hr creatinine clearance) from baseline to months 12 and 36 | From baseline to 12 and 36 months | 
| Decline in eGFR, sustained low eGFR, kidney transplantation, maintenance dialysis, and kidney death | Time to occurrence of sustained % decline in eGFR, sustained low eGFR, kidney transplantation, maintenance dialysis, and kidney death | Time to occurrence (from baseline) | 
| Maintenance dialysis, kidney transplantation, kidney death, and GFR < 15 ml/min | Individual and composite endpoints of maintenance dialysis, kidney transplantation, kidney death, and GFR < 15 ml/min at 12 and 36 months | At 12 and 36 months after randomization | 
| Change in body weight | Change in body weight from baseline to months 12 and 36 | From baseline to 12 and 36 months | 
| Change in body mass index | Change in body mass index from baseline to months 12 and 36 | From baseline to 12 and 36 months | 
| Change in waist circumference | Change in waist circumference from baseline to months 12 and 36 | From baseline to 12 and 36 months | 
| Medications to maintain optimal diabetes and blood pressure control | Number and dose of medications to maintain optimal diabetes and blood pressure control from baseline to months 12 and 36 | From baseline to 12 and 36 months | 
| Change in fasting glucose | Change in fasting glucose from baseline to months 12 and 36 | From baseline to 12 and 36 months | 
| Change in HbA1c | Change in HbA1c from baseline to months 12 and 36 | From baseline to 12 and 36 months | 
| Change in basal insulin | Change in basal insulin from baseline to months 12 and 36 | From baseline to 12 and 36 months | 
| Change in homeostasis model assessment (HOMA) scores | Change in homeostasis model assessment (HOMA) scores from baseline to months 12 and 36 | From baseline to 12 and 36 months | 
| Remission in type 2 diabetes | Achievement of partial or complete remission in type 2 diabetes by months 12 and 36 | At 12 and 36 months after randomization | 
| Change in blood pressure | Change in blood pressure from baseline to months 12 and 36 | From baseline to 12 and 36 months | 
| Hypoglycemic adverse events | Number of patients with confirmed or symptomatic hypoglycemic adverse events from baseline to months 12 and 36 | From baseline to 12 and 36 months | 
| Changes in total cholesterol, triglycerides, LDL and HDL levels | Changes in total cholesterol, triglycerides, LDL and HDL levels from baseline to months 12 and 36 | From baseline to 12 and 36 months | 
| Number of participants achieving LDL < 100 mg/dL and HDL > 40mg/dL | Number of participants achieving LDL < 100 mg/dL and HDL > 40mg/dL from baseline to months 12 and 36 | From baseline to 12 and 36 months | 
| Changes in serum calcium and phosphorus, | Changes in serum calcium and phosphorus from baseline to months 12 and 36 | From baseline to 12 and 36 months | 
| Change in parathyroid hormone (PTH) | Change in parathyroid hormone (PTH) from baseline to months 12 and 36 | From baseline to 12 and 36 months | 
| Change in mineral bone density | Change in mineral bone density from baseline to months 12 and 36 | From baseline to 12 and 36 months | 
| Change in quality of life | Change in quality of life measured by SF-36 questionnaire from baseline to months 12 and 36 | From baseline to 12 and 36 months | 
| Adverse events | Number of patients with adverse events from baseline to months 12 and 36 | From baseline to 12 and 36 months | 
| Acute kidney injury | Number of episodes of acute kidney injury from baseline to months 12 and 36 | From baseline to 12 and 36 months | 
| Adverse cardiovascular events (nonfatal stroke, nonfatal MI, cardiovascular death) | Composite of major adverse cardiovascular events (nonfatal stroke, nonfatal MI, cardiovascular death) from baseline to months 12 and 36 | From baseline to 12 and 36 months | 
| Mortality | Total mortality from baseline to months 12 and 36 | From baseline to 12 and 36 months | 
| Days hospitalized | Number of days hospitalized from baseline to months 12 and 36 | From baseline to 12 and 36 months | 
| Change in urinary volume | Change in urinary volume from baseline to months 12 and 36 | From baseline to 12 and 36 months | 
| Change in calcium and oxalate excretion | Change in calcium and oxalate excretion from baseline to months 12 and 36 | From baseline to 12 and 36 months | 
| High sensitivity c-reactive protein | Change in high sensitivity c-reactive protein from baseline to months 12 and 36 | From baseline to 12 and 36 months | 
| Change in muscle strength | Change in muscle strength using one repetition maximum (1-RM) from baseline to months12 and 36 | From baseline to 12 and 36 months | 
| Kidney volumes | Change in kidney volumes from baseline to months 12 and 36 | From baseline to 12 and 36 months | 
| Change in ventricular mass | Change in left and right ventricular mass from baseline to months 12 and 36 | From baseline to 12 and 36 months | 
| Change in ejection fraction | Change in left ventricular ejection fraction from baseline to months 12 and 36 | From baseline to 12 and 36 months | 
| Costs of care and health care utilization | Costs of care and health care utilization from baseline to months 12 and 36 | From baseline to 12 and 36 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Diabetes Mellitus, Type 2, Diabetes Mellitus, Obesity, Metabolic surgery, Gastric bypass, Diabetic kidney disease