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Randomized Study Comparing Metabolic Surgery With Intensive Medical Therapy to Treat Diabetic Kidney Disease (OBESE-DKD)

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ClinicalTrials.gov Identifier: NCT04626323
Recruitment Status : Recruiting
First Posted : November 12, 2020
Last Update Posted : May 28, 2021
Sponsor:
Information provided by (Responsible Party):
Ricardo Vitor Cohen, MD, Hospital Alemão Oswaldo Cruz

Study Description
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Brief Summary:

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.


Condition or disease Intervention/treatment Phase
Diabetes Mellitus, Type 2 Kidney Disease, Chronic Kidney Injury Procedure: Roux-en-Y gastric bypass Drug: Best medical treatment Phase 2

Detailed 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).

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.

Study Design
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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 60 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention 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)
Primary Purpose: Treatment
Official Title: Open, Randomized, Unicenter Study Comparing Metabolic Surgery With Intensive Medical Therapy to Treat Diabetic Kidney Disease
Actual Study Start Date : May 25, 2021
Estimated Primary Completion Date : December 2024
Estimated Study Completion Date : December 2024

Resource links provided by the National Library of Medicine


Arms and Interventions
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Arm Intervention/treatment
Experimental: RYGB (intervention 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.
 Procedure: Roux-en-Y gastric bypass
  1. Pneumoperitoneum closed with Veress needle
  2. Identification of Treitz angle
  3. Measurement of biliary loop (50 cm)
  4. Bowel transection with linear stapler (white load)
  5. Measurement of the alimentary limb (100 cm)
  6. Laterolateral Entero-anastomoses (white load)
  7. Construction of gastric pouch distant about 3 cm from the esophageal-gastric junction with stomach section in the small curvature.
  8. Linear cutting anastomosis (gastrojejunostomy) from about 1 to 1.2 cm
  9. Anastomosis integrity evaluation by methylene blue test and/or perioperative air.

Expected surgical time: 60 minutes

Other Name: RYGB

Drug: Best medical treatment
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 Name: BMT
Active Comparator: BMT (control arm).
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
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 Name: BMT


Outcome Measures
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Primary Outcome Measures :
  1. Mean differenceGlomerular filtration rate (GFR) [ Time Frame: At 12 and 36 months after randomization ]
    Mean difference in GFR between BMT and RYGB at the pre-specified time points of 12 and 36 months after randomization


Secondary Outcome Measures :
  1. Change in twenty-four hour urinary albumin/protein excretion [ Time Frame: From baseline to 12 and 36 months ]
    Change in 24h urinary albumin/protein excretion

  2. Improvements in micro- or macroalbuminuria [ Time Frame: From baseline to 12 and 36 months ]
    Proportion of patients who achieve improvements in micro- or macroalbuminuria from baseline to 12 and 36 months

  3. Change in CKD stage and CKD prognostic risk [ Time Frame: From baseline to 12 and 36 months ]
    Change in CKD stage and CKD prognostic risk from baseline to month 12 and 36

  4. Change in GFR, eGFR and 24 hr creatinine clearance [ Time Frame: From baseline to 12 and 36 months ]
    Change in GFR, eGFR and 24 hr creatinine clearance from baseline to months 12 and 36

  5. Proportion of participants with ≥30%, ≥40%, and ≥50% reduction in GFR measurements [ Time Frame: From baseline to 12 and 36 months ]
    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

  6. Decline in eGFR, sustained low eGFR, kidney transplantation, maintenance dialysis, and kidney death [ Time Frame: Time to occurrence (from baseline) ]
    Time to occurrence of sustained % decline in eGFR, sustained low eGFR, kidney transplantation, maintenance dialysis, and kidney death

  7. Maintenance dialysis, kidney transplantation, kidney death, and GFR < 15 ml/min [ Time Frame: At 12 and 36 months after randomization ]
    Individual and composite endpoints of maintenance dialysis, kidney transplantation, kidney death, and GFR < 15 ml/min at 12 and 36 months

  8. Change in body weight [ Time Frame: From baseline to 12 and 36 months ]
    Change in body weight from baseline to months 12 and 36

  9. Change in body mass index [ Time Frame: From baseline to 12 and 36 months ]
    Change in body mass index from baseline to months 12 and 36

  10. Change in waist circumference [ Time Frame: From baseline to 12 and 36 months ]
    Change in waist circumference from baseline to months 12 and 36

  11. Medications to maintain optimal diabetes and blood pressure control [ Time Frame: From baseline to 12 and 36 months ]
    Number and dose of medications to maintain optimal diabetes and blood pressure control from baseline to months 12 and 36

  12. Change in fasting glucose [ Time Frame: From baseline to 12 and 36 months ]
    Change in fasting glucose from baseline to months 12 and 36

  13. Change in HbA1c [ Time Frame: From baseline to 12 and 36 months ]
    Change in HbA1c from baseline to months 12 and 36

  14. Change in basal insulin [ Time Frame: From baseline to 12 and 36 months ]
    Change in basal insulin from baseline to months 12 and 36

  15. Change in homeostasis model assessment (HOMA) scores [ Time Frame: From baseline to 12 and 36 months ]
    Change in homeostasis model assessment (HOMA) scores from baseline to months 12 and 36

  16. Remission in type 2 diabetes [ Time Frame: At 12 and 36 months after randomization ]
    Achievement of partial or complete remission in type 2 diabetes by months 12 and 36

  17. Change in blood pressure [ Time Frame: From baseline to 12 and 36 months ]
    Change in blood pressure from baseline to months 12 and 36

  18. Hypoglycemic adverse events [ Time Frame: From baseline to 12 and 36 months ]
    Number of patients with confirmed or symptomatic hypoglycemic adverse events from baseline to months 12 and 36

  19. Changes in total cholesterol, triglycerides, LDL and HDL levels [ Time Frame: From baseline to 12 and 36 months ]
    Changes in total cholesterol, triglycerides, LDL and HDL levels from baseline to months 12 and 36

  20. Number of participants achieving LDL < 100 mg/dL and HDL > 40mg/dL [ Time Frame: From baseline to 12 and 36 months ]
    Number of participants achieving LDL < 100 mg/dL and HDL > 40mg/dL from baseline to months 12 and 36

  21. Changes in serum calcium and phosphorus, [ Time Frame: From baseline to 12 and 36 months ]
    Changes in serum calcium and phosphorus from baseline to months 12 and 36

  22. Change in parathyroid hormone (PTH) [ Time Frame: From baseline to 12 and 36 months ]
    Change in parathyroid hormone (PTH) from baseline to months 12 and 36

  23. Change in mineral bone density [ Time Frame: From baseline to 12 and 36 months ]
    Change in mineral bone density from baseline to months 12 and 36

  24. Change in quality of life [ Time Frame: From baseline to 12 and 36 months ]
    Change in quality of life measured by SF-36 questionnaire from baseline to months 12 and 36

  25. Adverse events [ Time Frame: From baseline to 12 and 36 months ]
    Number of patients with adverse events from baseline to months 12 and 36

  26. Acute kidney injury [ Time Frame: From baseline to 12 and 36 months ]
    Number of episodes of acute kidney injury from baseline to months 12 and 36

  27. Adverse cardiovascular events (nonfatal stroke, nonfatal MI, cardiovascular death) [ Time Frame: From baseline to 12 and 36 months ]
    Composite of major adverse cardiovascular events (nonfatal stroke, nonfatal MI, cardiovascular death) from baseline to months 12 and 36

  28. Mortality [ Time Frame: From baseline to 12 and 36 months ]
    Total mortality from baseline to months 12 and 36

  29. Days hospitalized [ Time Frame: From baseline to 12 and 36 months ]
    Number of days hospitalized from baseline to months 12 and 36

  30. Change in urinary volume [ Time Frame: From baseline to 12 and 36 months ]
    Change in urinary volume from baseline to months 12 and 36

  31. Change in calcium and oxalate excretion [ Time Frame: From baseline to 12 and 36 months ]
    Change in calcium and oxalate excretion from baseline to months 12 and 36

  32. High sensitivity c-reactive protein [ Time Frame: From baseline to 12 and 36 months ]
    Change in high sensitivity c-reactive protein from baseline to months 12 and 36

  33. Change in muscle strength [ Time Frame: From baseline to 12 and 36 months ]
    Change in muscle strength using one repetition maximum (1-RM) from baseline to months12 and 36

  34. Kidney volumes [ Time Frame: From baseline to 12 and 36 months ]
    Change in kidney volumes from baseline to months 12 and 36

  35. Change in ventricular mass [ Time Frame: From baseline to 12 and 36 months ]
    Change in left and right ventricular mass from baseline to months 12 and 36

  36. Change in ejection fraction [ Time Frame: From baseline to 12 and 36 months ]
    Change in left ventricular ejection fraction from baseline to months 12 and 36

  37. Costs of care and health care utilization [ Time Frame: From baseline to 12 and 36 months ]
    Costs of care and health care utilization from baseline to months 12 and 36


Eligibility Criteria
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Information from the National Library of Medicine

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Ages Eligible for Study:   30 Years to 70 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04626323


Contacts
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Contact: Cristina M Aboud, RN, MSc +551135491187 cmamedio@haoc.com.br

Locations
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Brazil
Centro especializado em Obesidade e Diabetes do Hospital Alemão Oswaldo Cruz Recruiting
Sao Paulo, São Paulo, Brazil, 01323-020
Contact: Cristina M Aboud, RN, MSc    1135491187    cmamedio@haoc.com.br   
Sponsors and Collaborators
Hospital Alemão Oswaldo Cruz
Investigators
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Principal Investigator: Ricardo V Cohen, MD, PhD Oswaldo Cruz German Hospital
More Information
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Additional Information:

Publications of Results:
(IHME) IfHMaE. Findings from the Global Burden of Disease Study 2017. Seattle, WA2018.
World Health Organization Diabetes. 2018; https://www.who.int/news-room/fact-sheets/detail/diabetes.

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Responsible Party: Ricardo Vitor Cohen, MD, Ricardo Vitor Cohen, MD, PhD, Hospital Alemão Oswaldo Cruz
ClinicalTrials.gov Identifier: NCT04626323    
Other Study ID Numbers: OBESE-DKD
CAAE - 37013420500000070 ( Other Identifier: Institutional Review Board )
First Posted: November 12, 2020    Key Record Dates
Last Update Posted: May 28, 2021
Last Verified: May 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Ricardo Vitor Cohen, MD, Hospital Alemão Oswaldo Cruz:
Diabetes Mellitus, Type 2
Diabetes Mellitus
Obesity
 Metabolic surgery
Gastric bypass
Diabetic kidney disease
Additional relevant MeSH terms:
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Kidney Diseases
Diabetic Nephropathies
Renal Insufficiency, Chronic
Diabetes Mellitus
Diabetes Mellitus, Type 2
Glucose Metabolism Disorders
 Metabolic Diseases
Endocrine System Diseases
Urologic Diseases
Diabetes Complications
Renal Insufficiency