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Impact of Metabolic Surgery on Pancreatic, Renal and Cardiovascular Health in Youth With Type 2 Diabetes (IMPROVE-T2D)

Primary Purpose

Type 2 Diabetes Mellitus, Obesity, Bariatric Surgery Candidate

Status
Recruiting
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
Aminohippurate Sodium Inj 20%
Iohexol Inj 300 mg/mL
Vertical Sleeve Gastrectomy
Renal Biopsy
Sponsored by
University of Colorado, Denver
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional diagnostic trial for Type 2 Diabetes Mellitus

Eligibility Criteria

12 Years - 21 Years (Child, Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Obese youth with T2D (≥50 kg) scheduled for VSG
  • Weight <550 lbs.
  • BMI ≥ 35 kg/m2
  • Age 12-21 years
  • HbA1c ≤ 12%

Exclusion Criteria:

  • T2D onset (diagnosis) > 18 years of age
  • Prepubertal
  • Anemia
  • Seafood or iodine allergy
  • Pregnancy or breastfeeding
  • Claustrophobia, implantable devices (MRI contraindications)
  • Recent diabetic ketoacidosis or hyperosmolar hyperglycemia
  • Other causes of diabetes other than T2D
  • Diuretics, sodium-glucose co-transport (SGLT) 2 or 1 blockers, daily NSAIDs or aspirin, sulfonamides, procaine, thiazolsulfone or probenecid, atypical antipsychotics or regular use of oral steroids

Additional exclusion criteria for participants undergoing optional kidney biopsy:

  • Evidence of bleeding disorder or complications from bleeding
  • Use of aspirin, NSAIDS or other blood thinner that cannot be safely stopped for a sufficient time period before and after the biopsy so as to add no additional risk of bleeding
  • Blood urea nitrogen (BUN) > 80 gm/dL
  • INR > 1.4
  • PTT > 35 seconds
  • Hemoglobin (Hgb) < 10 mg/dL
  • Platelet count < 100,000 / µL
  • Uncontrolled or difficult to control hypertension (> 150/90 mmHg at the day of biopsy)
  • eGFR < 40 mL/min/1.73m2
  • Single kidney (either by history, documented by prior imaging or ultrasound performed prior to the biopsy)
  • > 2 cm discrepancy between left and right kidney sizes based on largest longitudinal diameter determined by ultrasound performed prior to the biopsy.
  • Kidney size: One or both kidneys < 9 cm
  • Hydronephrosis or other important renal ultrasound findings such as significant stone disease
  • Any evidence of a current urinary tract infection as indicated on day of biopsy
  • Clinical evidence of non-diabetic renal disease
  • Positive urine pregnancy test or pregnancy

Sites / Locations

  • Children's Hospital ColoradoRecruiting

Arms of the Study

Arm 1

Arm Type

Other

Arm Label

Clinical Investigation

Arm Description

Participants will include youth who are scheduled for, and will undergo, vertical sleeve gastrectomy (VSG) surgery at the Bariatric Surgery Clinic at Children's Hospital of Colorado. To understand how bariatric surgery affects renal function, all participants will undergo assessment of Glomerular Filtration Rate, (Iohexol Inj 300 mg/mL) and Effective Renal Plasma Flow (Aminohippurate Sodium Inj 20%). In addition, participants will undergo imaging assessment that includes renal Blood Oxygen Level Dependent (BOLD) and Arterial Spin Labeling (ASL) MRI.

Outcomes

Primary Outcome Measures

Pancreatic β-cell function
Measured by Mixed Meal Tolerance Test (MMTT)
Pancreatic β-cell function
Measured by blood draws during/after hyperglycemic clamp
Effective Renal Plasma Flow (ERPF)
Measured by PAH clearance
Glomerular Filtration Rate (GFR)
Measured by iohexol clearance

Secondary Outcome Measures

Renal Perfusion
Measured by Arterial Spin Labeling (ASL) MRI
Renal Oxygenation
Measured by Blood Oxygen Level Dependent (BOLD) MRI
Aortic Stiffness & Wall Shear Stress
Measured by Aortic MRI

Full Information

First Posted
August 1, 2018
Last Updated
February 7, 2023
Sponsor
University of Colorado, Denver
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1. Study Identification

Unique Protocol Identification Number
NCT03620773
Brief Title
Impact of Metabolic Surgery on Pancreatic, Renal and Cardiovascular Health in Youth With Type 2 Diabetes
Acronym
IMPROVE-T2D
Official Title
IMPROVE-T2D Study: Impact of Metabolic Surgery on Pancreatic, Renal and Cardiovascular Health in Youth With Type 2 Diabetes
Study Type
Interventional

2. Study Status

Record Verification Date
February 2023
Overall Recruitment Status
Recruiting
Study Start Date
October 1, 2018 (Actual)
Primary Completion Date
August 1, 2024 (Anticipated)
Study Completion Date
August 1, 2024 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
University of Colorado, Denver

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No

5. Study Description

Brief Summary
Type 2 diabetes (T2D) in youth is increasing in prevalence in parallel with the obesity epidemic. In the US, almost half of patients with renal failure have DKD, and ≥80% have T2D. Compared to adult-onset T2D, youth with T2D have a more aggressive phenotype with greater insulin resistance (IR), more rapid β-cell decline and higher prevalence of diabetic kidney disease (DKD), arguing for separate and dedicated studies in youth-onset T2D. Early DKD is characterized by changes in intrarenal hemodynamic function, including increased renal plasma flow (RPF) and glomerular pressure with resultant hyperfiltration, is common in Y-T2D, and predicts progressive DKD. Studies evaluating the two currently approved medications for treating T2D in youth (metformin and insulin) have shown these medications are not able to improve β-cell function over time in the youth. However, recent evidence suggests that bariatric surgery in adults is associated with improvements in diabetes outcomes, and even T2D remission in many patients. Limited data in youth also supports the benefits of bariatric surgery, regarding weight loss, glycemic control in T2D, and cardio-renal health. While weight loss is important, the acute effect of bariatric surgery on factors such as insulin resistance likely includes weight loss-independent mechanisms. A better understanding of the effects of bariatric surgery on pancreatic function, intrarenal hemodynamics, renal O2 and cardiovascular function is critical to help define mechanisms of surgical benefits, to help identify potential novel future non-surgical approaches to prevent pancreatic failure, DKD and cardiovascular disease. The investigators' overarching hypotheses are that: 1) Y-T2D is associated with IR, pancreatic dysfunction, intrarenal hemodynamic dysfunction, elevated renal O2 consumption and cardiovascular dysfunction which improve with bariatric surgery, 2) The early effect of bariatric surgery on intrarenal hemodynamics is mediated by improvement in IR and weight loss. To address these hypotheses, the investigators will measure GFR, RPF, glomerular pressure and renal O2, in addition to aortic stiffness, β-cell function and insulin sensitivity in youth ages 12-21 with T2D (n=30) before and after vertical sleeve gastrectomy (VSG). To further investigate the mechanisms of renal damage in youth with T2D, two optional procedures are included in the study prior to vertical sleeve gastrectomy: 1) kidney biopsy procedure and 2) induction of induced pluripotent stem cells (iPSCs) to assess morphometrics and genetic expression of renal tissue.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Type 2 Diabetes Mellitus, Obesity, Bariatric Surgery Candidate, Nephropathy, Diabetic Kidney Disease, Diabetes Mellitus, Type 2, Diabetes Mellitus, Diabetes Complications, Weight Loss, Diabetic Nephropathies, Adolescent Obesity, Pediatric Obesity

7. Study Design

Primary Purpose
Diagnostic
Study Phase
Phase 1, Phase 2
Interventional Study Model
Single Group Assignment
Model Description
All participants in this study will receive the same intervention.
Masking
None (Open Label)
Allocation
N/A
Enrollment
30 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Clinical Investigation
Arm Type
Other
Arm Description
Participants will include youth who are scheduled for, and will undergo, vertical sleeve gastrectomy (VSG) surgery at the Bariatric Surgery Clinic at Children's Hospital of Colorado. To understand how bariatric surgery affects renal function, all participants will undergo assessment of Glomerular Filtration Rate, (Iohexol Inj 300 mg/mL) and Effective Renal Plasma Flow (Aminohippurate Sodium Inj 20%). In addition, participants will undergo imaging assessment that includes renal Blood Oxygen Level Dependent (BOLD) and Arterial Spin Labeling (ASL) MRI.
Intervention Type
Drug
Intervention Name(s)
Aminohippurate Sodium Inj 20%
Other Intervention Name(s)
Aminohippuric acid, Para-aminohippurate, Sodium 4-amino hippurate (PAH) inj 20% 2g/10 mL
Intervention Description
Diagnostic aid/agent used to measure effective renal plasma flow (ERPF)
Intervention Type
Drug
Intervention Name(s)
Iohexol Inj 300 mg/mL
Other Intervention Name(s)
omnipaque 300
Intervention Description
Diagnostic aid/agent used to measure glomerular filtration rate (GFR)
Intervention Type
Procedure
Intervention Name(s)
Vertical Sleeve Gastrectomy
Other Intervention Name(s)
Bariatric Surgery
Intervention Description
Participants will undergo vertical sleeve gastrectomy surgery, a laparoscopic bariatric surgery procedure designed for weight loss in obese patients
Intervention Type
Procedure
Intervention Name(s)
Renal Biopsy
Other Intervention Name(s)
Kidney Biopsy
Intervention Description
Minimally invasive outpatient procedure in interventional radiology to obtain renal tissue cores.
Primary Outcome Measure Information:
Title
Pancreatic β-cell function
Description
Measured by Mixed Meal Tolerance Test (MMTT)
Time Frame
4 hours (MMTT)
Title
Pancreatic β-cell function
Description
Measured by blood draws during/after hyperglycemic clamp
Time Frame
4 hours (hyperglycemic clamp)
Title
Effective Renal Plasma Flow (ERPF)
Description
Measured by PAH clearance
Time Frame
4 hours
Title
Glomerular Filtration Rate (GFR)
Description
Measured by iohexol clearance
Time Frame
4 hours
Secondary Outcome Measure Information:
Title
Renal Perfusion
Description
Measured by Arterial Spin Labeling (ASL) MRI
Time Frame
10 min
Title
Renal Oxygenation
Description
Measured by Blood Oxygen Level Dependent (BOLD) MRI
Time Frame
60 min
Title
Aortic Stiffness & Wall Shear Stress
Description
Measured by Aortic MRI
Time Frame
30 min
Other Pre-specified Outcome Measures:
Title
Podocyte numerical density and number per glomerulus
Description
Measured by light microscopy from tissue obtained by renal biopsy
Time Frame
4 hours
Title
Foot process width of glomeruli
Description
Measured from tissue obtained by renal biopsy
Time Frame
4 hours
Title
Detachment and endothelial fenestration of glomeruli
Description
Measured by electron microscopy from tissue obtained by renal biopsy
Time Frame
4 hours
Title
Podocyte volume of glomeruli
Description
Measured by electron microscopy from tissue obtained by renal biopsy
Time Frame
4 hours
Title
Number and identity of RNA in kidney cells
Description
Measured from tissue obtained by renal biopsy
Time Frame
4 hours
Title
Epigenetic profiling
Description
Measured from tissue obtained by renal biopsy
Time Frame
4 hours

10. Eligibility

Sex
All
Minimum Age & Unit of Time
12 Years
Maximum Age & Unit of Time
21 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Obese youth with T2D (≥50 kg) scheduled for VSG Weight <550 lbs. BMI ≥ 35 kg/m2 Age 12-21 years HbA1c ≤ 12% Exclusion Criteria: T2D onset (diagnosis) > 18 years of age Prepubertal Anemia Seafood or iodine allergy Pregnancy or breastfeeding Claustrophobia, implantable devices (MRI contraindications) Recent diabetic ketoacidosis or hyperosmolar hyperglycemia Other causes of diabetes other than T2D Diuretics, sodium-glucose co-transport (SGLT) 2 or 1 blockers, daily NSAIDs or aspirin, sulfonamides, procaine, thiazolsulfone or probenecid, atypical antipsychotics or regular use of oral steroids Additional exclusion criteria for participants undergoing optional kidney biopsy: Evidence of bleeding disorder or complications from bleeding Use of aspirin, NSAIDS or other blood thinner that cannot be safely stopped for a sufficient time period before and after the biopsy so as to add no additional risk of bleeding Blood urea nitrogen (BUN) > 80 gm/dL INR > 1.4 PTT > 35 seconds Hemoglobin (Hgb) < 10 mg/dL Platelet count < 100,000 / µL Uncontrolled or difficult to control hypertension (> 150/90 mmHg at the day of biopsy) eGFR < 40 mL/min/1.73m2 Single kidney (either by history, documented by prior imaging or ultrasound performed prior to the biopsy) > 2 cm discrepancy between left and right kidney sizes based on largest longitudinal diameter determined by ultrasound performed prior to the biopsy. Kidney size: One or both kidneys < 9 cm Hydronephrosis or other important renal ultrasound findings such as significant stone disease Any evidence of a current urinary tract infection as indicated on day of biopsy Clinical evidence of non-diabetic renal disease Positive urine pregnancy test or pregnancy
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Susan Gross, MS, RD
Phone
720-777-6143
Email
susan.gross@childrenscolorado.org
First Name & Middle Initial & Last Name or Official Title & Degree
Petter Bjornstad, MD
Phone
720-777-4659
Email
petter.bjornstad@childrenscolorado.org
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Petter Bjornstad, MD
Organizational Affiliation
University of Colorado School of Medicine
Official's Role
Principal Investigator
Facility Information:
Facility Name
Children's Hospital Colorado
City
Aurora
State/Province
Colorado
ZIP/Postal Code
80045
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Petter Bjornstad, MD
Phone
720-777-4659
Email
petter.bjornstad@childrenscolorado.org
First Name & Middle Initial & Last Name & Degree
Petter Bjornstad, M.D.
First Name & Middle Initial & Last Name & Degree
Kristin Nadeau, M.D.

12. IPD Sharing Statement

Plan to Share IPD
Undecided

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Impact of Metabolic Surgery on Pancreatic, Renal and Cardiovascular Health in Youth With Type 2 Diabetes

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