Copeptin in Adolescent Participants With Type 1 Diabetes and Early Renal Hemodynamic Function (CASPER)

• ClinicalTrials.gov Identifier: NCT03618420
• Recruitment Status: Completed
• First Posted: August 7, 2018
• Results First Posted: August 31, 2021
• Last Update Posted: April 20, 2022
• Sponsor: University of Colorado, Denver
• Information provided by (Responsible Party): University of Colorado, Denver

Tracking Information

• First Submitted Date: August 1, 2018
• First Posted Date: August 7, 2018
• Results First Submitted Date: August 5, 2021
• Results First Posted Date: August 31, 2021
• Last Update Posted Date: April 20, 2022
• Actual Study Start Date: October 1, 2018
• Actual Primary Completion Date: October 19, 2019 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: March 23, 2022)

• Copeptin Levels [ Time Frame: 4 hours ]
  Measured by fasting blood draw; Copeptin will be measured by ultrasensitive assays on KRYPTOR Compact Plus analyzers using the commercial sandwich immunoluminometric assays (Thermo Fisher Scientific, Waltham, MA). The copeptin assay has a lower limit of detection of 0.9 pmol/L, and a sensitivity of <2pmol/L. Elevated copeptin will be defined as >13pmol/L, which is >97.5th percentile for healthy adults (68).
• Effective Renal Plasma Flow (ERPF) [ Time Frame: 4 hours ]
  Measured by para-aminohippurate (PAH) clearance; An intravenous (IV) line was placed, and participants were asked to empty their bladders. Spot plasma and urine samples were collected prior PAH infusion. PAH (2 g/10 mL, prepared at the University of Minnesota, with a dose of [weight in kg]/75 × 4.2 mL; IND #140129) was given slowly over 5 min followed by a continuous infusion of 8 mL of PAH and 42 mL of normal saline at a rate of 24 mL/h for 2 h. After an equilibration period, blood was drawn at 90 and 120 min, and ERPF was calculated as PAH clearance divided by the estimated extraction ratio of PAH, which varies by the level of GFR (13). We report absolute ERPF (mL/min) in the main analyses because the practice of indexing ERPF for body surface underestimates hyperperfusion, and body surface area (BSA) calculations introduce noise into the clearance measurements.
• Glomerular Filtration Rate (GFR) [ Time Frame: 4 hours ]
  Measured by iohexol clearance; An intravenous (IV) line was placed, and participants were asked to empty their bladders. Spot plasma and urine samples were collected prior to iohexol infusion. Iohexol was administered through bolus IV injection (5 mL of 300 mg/mL; Omnipaque 300, GE Healthcare). An equilibration period of 120 min was used and blood collections for iohexol plasma disappearance were drawn at +120, +150, +180, +210, +240 min (11). Because the Brøchner-Mortensen equation underestimates high values of GFR, the Jødal-Brøchner-Mortensen equation was used to calculate the GFR (12). We report absolute GFR (mL/min) in the main analyses because the practice of indexing GFR for body surface underestimates hyperfiltration, and body surface area (BSA) calculations introduce noise into the clearance measurements.

Original Primary Outcome Measures (submitted: August 1, 2018)

• Copeptin levels [ Time Frame: 4 hours ]
  Measured by fasting blood draw
• Effective Renal Plasma Flow (ERPF) [ Time Frame: 4 hours ]
  Measured by PAH clearance
• Glomerular Filtration Rate (GFR) [ Time Frame: 4 hours ]
  Measured by Ioxhexal clearance

Current Secondary Outcome Measures (submitted: March 23, 2022)

• Renal Perfusion [ Time Frame: 10 min ]
  Measured by Arterial Spin Labeling (ASL) MRI; ASL MRI: ROI analysis will be used to estimate (delta) M (difference in signal intensity between non-selective and selective inversion images). Using the same ROI, M0 will be estimated from the proton density image. T1 measurements from the same ROI will be obtained by fitting the signal intensity vs. inversion time data as described previously (104) using XLFit (ID Business Solutions Ltd., UK) or T1 maps created using MRI Mapper (Beth Israel Deaconess Medical Center, Boston). Partition coefficient will be assumed to be 0.8 ml/gm (105, 106). These values will then be used to estimate regional blood flow.
• Renal Oxygenation [ Time Frame: 60 min ]
  Measured by Blood Oxygen Level Dependent (BOLD) MRI; Regions of interest (ROI) analysis for BOLD MRI will be performed on a Leonardo Workstation (Siemens Medical Systems, Germany). Typically, 1 to 3 regions in each, cortex and medulla, per kidney per slice will be defined leading to a total of about 10 ROIs per region (cortex and medulla) per subject. The mean and standard deviation of these 10 measurements will be used a R2* measurement for the region, for the subject and for that time point. These data are used to calculate kidney oxygen availability (R2*), which is the BOLD-MRI outcome.

Original Secondary Outcome Measures (submitted: August 1, 2018)

• Renal Perfusion [ Time Frame: 10 min ]
  Measured by Arterial Spin Labeling (ASL) MRI
• Renal Oxygenation [ Time Frame: 60 min ]
  Measured by Blood Oxygen Level Dependent (BOLD) MRI

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Copeptin in Adolescent Participants With Type 1 Diabetes and Early Renal Hemodynamic Function
• Official Title: CASPER Study: Copeptin in Adolescent Participants With Type 1 Diabetes and Early Renal Hemodynamic Function

Brief Summary

Over 1.25 million Americans have type 1 diabetes (T1D), increasing risk for early death from cardiorenal disease. The strongest risk factor for cardiovascular disease (CVD) and mortality in T1D is diabetic kidney disease (DKD). Current treatments, such as control of hyperglycemia and hypertension, are beneficial, but only partially protect against DKD.

Hyperfiltration is common in youth with T1D, and predicts progressive DKD. Hyperfiltration is also associated with early changes in intrarenal hemodynamic function, including increased renal plasma flow (RPF) and glomerular pressure. Intrarenal hemodynamic function is strongly influenced by the renin-angiotensin-aldosterone system (RAAS), which is also considered a key player in the pathogenesis of DKD. Preliminary data demonstrate differences in intrarenal hemodynamic function and RAAS activation in early and advanced DKD in T1D. However, the pathophysiology contributing to the differences observed in RAAS activation and intrarenal hemodynamic function in T1D are poorly defined Animal research demonstrates that arginine vasopressin (AVP) acts directly to modify intrarenal hemodynamic function, but also indirectly by activating RAAS. Preliminary data suggest that elevated copeptin, a marker of AVP, which predicts DKD in T1D adults, independently of other risk factors. However, no human studies to date have examined how copeptin relates to intrarenal hemodynamic function in early DKD in T1D. A better understanding of this relationship is critical to inform development of new therapies targeting the AVP system in T1D. Accordingly, in this study, the investigators propose to define the relationship between copeptin and intrarenal hemodynamics in early stages of DKD, by studying copeptin levels, renal plasma flow, and glomerular filtration in youth (n=50) aged 12-21 y with T1D duration < 10 y.

• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 1; Phase 2

Study Design

Allocation: N/A
Intervention Model: Single Group Assignment
Intervention Model Description:

All study participants will receive the same intervention.

Masking: None (Open Label)
Primary Purpose: Diagnostic

Condition

• Diabetes Mellitus, Type 1
• Nephropathy
• Diabetic Nephropathies
• Juvenile Diabetes
• Diabetes Mellitus Complication
• Autoimmune Diabetes
• Type 1 Diabetes Mellitus

Intervention

• Drug: Aminohippurate Sodium Inj 20%
  Diagnostic aid/agent used to measure effective renal plasma flow (ERPF)
  Other Names:

  • Aminohippuric acid
  • Para-aminohippurate (PAH)
  • Sodium 4-amino hippurate (PAH) inj 20% 2g/10 mL
• Drug: Iohexol Inj 300 mg/mL
  Diagnostic aid/agent used to measure glomerular filtration rate (GFR)
  Other Name: omnipaque 300

Study Arms

Clinical Investigation

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 Dual X-Ray Absorptiometry (DXA), renal Blood Oxygen Level Dependent (BOLD) and Arterial Spin Labeling (ASL) MRI.

Interventions:

• Drug: Aminohippurate Sodium Inj 20%
• Drug: Iohexol Inj 300 mg/mL

Publications *

• Vigers T, Vinovskis C, Li LP, Prasad P, Heerspink H, D'Alessandro A, Reisz JA, Piani F, Cherney DZ, van Raalte DH, Nadeau KJ, Pavkov ME, Nelson RG, Pyle L, Bjornstad P. Plasma levels of carboxylic acids are markers of early kidney dysfunction in young people with type 1 diabetes. Pediatr Nephrol. 2022 May 4. doi: 10.1007/s00467-022-05531-3. [Epub ahead of print]
• Vinovskis C, Li LP, Prasad P, Tommerdahl K, Pyle L, Nelson RG, Pavkov ME, van Raalte D, Rewers M, Pragnell M, Mahmud FH, Cherney DZ, Johnson RJ, Nadeau KJ, Bjornstad P. Relative Hypoxia and Early Diabetic Kidney Disease in Type 1 Diabetes. Diabetes. 2020 Dec;69(12):2700-2708. doi: 10.2337/db20-0457. Epub 2020 Jul 31.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: August 1, 2018): 50
• Original Estimated Enrollment: Same as current
• Actual Study Completion Date: August 1, 2021
• Actual Primary Completion Date: October 19, 2019 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Antibody+ T1D with <10 yr duration
• Age 12-21 years
• BMI ≥ 5%ile
• Weight<350 lbs and > 57 lbs.
• No anemia
• HbA1c <12%

Exclusion Criteria:

• Severe illness, recent diabetic ketoacidosis (DKA)
• Estimated Glomerular Filtration Rate (eGFR) <60ml/min/1.73m2 or creatinine > 1.5mg/dl or history of ACR≥300mg/g
• Anemia or allergy to shellfish or iodine
• Pregnancy or nursing
• MRI scanning contraindications (claustrophobia, implantable devices, >350 lbs)
• Angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARB), diuretics, sodium-glucose co-transport (SGLT) 2 or 1 blockers, daily NSAIDs or aspirin, sulfonamides, procaine, thiazolsulfone or probenecid, atypical antipsychotics and steroids

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 12 Years to 21 Years (Child, Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT03618420
• Other Study ID Numbers: 17-0820
• Has Data Monitoring Committee: No

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: Undecided

• Responsible Party: University of Colorado, Denver
• Study Sponsor: University of Colorado, Denver
• Collaborators: Not Provided

Investigators

• Principal Investigator: Petter Bjornstad, MD; University of Colorado School of Medicine

• PRS Account: University of Colorado, Denver
• Verification Date: March 2022