Trial Outcomes & Findings for Copeptin in Adolescent Participants With Type 1 Diabetes and Early Renal Hemodynamic Function (NCT NCT03618420)

Results Overview

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).

Recruitment status

COMPLETED

Study phase

PHASE1/PHASE2

Target enrollment

50 participants

Primary outcome timeframe

4 hours

Results posted on

2022-04-20

Participant Flow

Participant milestones

Participant milestones
Measure	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. Aminohippurate Sodium Inj 20%: Diagnostic aid/agent used to measure effective renal plasma flow (ERPF) Iohexol Inj 300 mg/mL: Diagnostic aid/agent used to measure glomerular filtration rate (GFR)
Overall Study STARTED	50
Overall Study COMPLETED	50
Overall Study NOT COMPLETED	0

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

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

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Clinical Investigation n=50 Participants 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. Aminohippurate Sodium Inj 20%: Diagnostic aid/agent used to measure effective renal plasma flow (ERPF) Iohexol Inj 300 mg/mL: Diagnostic aid/agent used to measure glomerular filtration rate (GFR)
Age, Continuous	16.0 years STANDARD_DEVIATION 3 • n=5 Participants
Sex: Female, Male Female	25 Participants n=5 Participants
Sex: Female, Male Male	25 Participants n=5 Participants
Race/Ethnicity, Customized Black non-Hispanic	1 Participants n=5 Participants
Race/Ethnicity, Customized Hispanic	3 Participants n=5 Participants
Race/Ethnicity, Customized White non-Hispanic	46 Participants n=5 Participants

PRIMARY outcome

Timeframe: 4 hours

Population: The overall number of participants analyzed for the outcome measure Copeptin levels is 49 because of an assay issue, specifically one of the samples failed during quality control.

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).

Outcome measures

Outcome measures
Measure	Clinical Investigation n=49 Participants 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. Aminohippurate Sodium Inj 20%: Diagnostic aid/agent used to measure effective renal plasma flow (ERPF) Iohexol Inj 300 mg/mL: Diagnostic aid/agent used to measure glomerular filtration rate (GFR)
Copeptin Levels	8.3 pmol/L Standard Deviation 5.0

PRIMARY outcome

Timeframe: 4 hours

Population: The overall number of participants analyzed for the outcome measure ERPF is 37 because PAH was unavailable for several of the first study visits.

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.

Outcome measures

Outcome measures
Measure	Clinical Investigation n=37 Participants 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. Aminohippurate Sodium Inj 20%: Diagnostic aid/agent used to measure effective renal plasma flow (ERPF) Iohexol Inj 300 mg/mL: Diagnostic aid/agent used to measure glomerular filtration rate (GFR)
Effective Renal Plasma Flow (ERPF)	820 ml/min Standard Deviation 125

PRIMARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Clinical Investigation n=50 Participants 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. Aminohippurate Sodium Inj 20%: Diagnostic aid/agent used to measure effective renal plasma flow (ERPF) Iohexol Inj 300 mg/mL: Diagnostic aid/agent used to measure glomerular filtration rate (GFR)
Glomerular Filtration Rate (GFR)	189 ml/min Standard Deviation 40

SECONDARY outcome

Timeframe: 10 min

Population: The overall number of participants analyzed for the outcome measure Renal Perfusion is 45 because scans did not meet the high quality control standard of our MRI reader and thus were omitted.

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.

Outcome measures

Outcome measures
Measure	Clinical Investigation n=45 Participants 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. Aminohippurate Sodium Inj 20%: Diagnostic aid/agent used to measure effective renal plasma flow (ERPF) Iohexol Inj 300 mg/mL: Diagnostic aid/agent used to measure glomerular filtration rate (GFR)
Renal Perfusion	180 ml/min/100g Standard Deviation 39

SECONDARY outcome

Timeframe: 60 min

Population: The overall number of participants analyzed for the outcome measure Renal Oxygenation is 41 because scans did not meet the high quality control standard of our MRI reader and thus were omitted.

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.

Outcome measures

Outcome measures
Measure	Clinical Investigation n=41 Participants 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. Aminohippurate Sodium Inj 20%: Diagnostic aid/agent used to measure effective renal plasma flow (ERPF) Iohexol Inj 300 mg/mL: Diagnostic aid/agent used to measure glomerular filtration rate (GFR)
Renal Oxygenation	22.7 s^-1 Standard Deviation 2.2

Adverse Events

Clinical Investigation

Serious events: 0 serious events

Other events: 2 other events

Deaths: 0 deaths

Serious adverse events

Adverse event data not reported

Other adverse events

Other adverse events
Measure	Clinical Investigation n=50 participants at risk 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. Aminohippurate Sodium Inj 20%: Diagnostic aid/agent used to measure effective renal plasma flow (ERPF) Iohexol Inj 300 mg/mL: Diagnostic aid/agent used to measure glomerular filtration rate (GFR)
Vascular disorders Vasovagal syncope	2.0% 1/50 • Adverse events were collected over 1 month post procedure (since this was a cross-sectional study).
Nervous system disorders Headache/lightheadedness/nausea	2.0% 1/50 • Adverse events were collected over 1 month post procedure (since this was a cross-sectional study).

Additional Information

Petter Bjornstad, M.D., Assistant Professor of Pediatrics and Medicine

University of Colorado School of Medicine

Phone: 7207774659

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place