Phase 1 Trial of Arginine Hydrochloride for the Management of Diabetic Ketoacidosis in Type 2 Diabetes
Trial statusRecruiting
Trial phasePhase 1, Phase 2
Trial typeInterventional
Biological sexAll
Age18+
SponsorDavid K Carroll
About this trial
Diabetic ketoacidosis (DKA) is increasingly recognized in adults with "ketone-prone" type 2 diabetes. In many of these patients, the pancreas can still make insulin but becomes temporarily "stunned" during severe, prolonged high blood sugar. Arginine is a naturally occurring amino acid that can trigger the pancreas to release its own insulin when glucose is high. It is FDA-approved for other uses and has been given intravenously for decades with a strong safety record. Whether a single arginine infusion given early during DKA can safely boost the body's insulin and speed recovery has not been tested.
This randomized, double-blind, placebo-controlled, phase 1/2 trial will enroll 60 adults who present to one of four Detroit-area emergency departments with DKA consistent with ketone-prone type 2 diabetes (high glucose and significant ketones). Participants will receive standard DKA care ordered by their clinicians. In addition, under blinded conditions they will receive either arginine hydrochloride 30 grams (in 300 mL) or placebo (normal saline), infused intravenously over 30 minutes as early as feasible after DKA is recognized.
The main question is whether arginine increases endogenous (self-made) insulin soon after infusion. We will measure C-peptide (a marker released in equal amounts with insulin) and glucose at 10, 30, and 90 minutes after the start of the infusion and calculate the C-peptide/glucose ratio. Secondary measures include the rate of ketone (β-hydroxybutyrate) clearance and the total insulin dose required in the first 24 hours. Additional blood tests will examine arginine and related amino acids, and a small sample of platelets will be used to explore mitochondrial function. Safety will be closely monitored during and after the infusion, and participants will be contacted at 90 days to assess for any delayed problems.
Potential risks include temporary flushing, nausea, or headache; the infusion can be stopped at any time if needed. Potential benefits include faster resolution of ketosis and reduced insulin needs, but benefits cannot be guaranteed for individual participants.
Eligibility criteria
This trial does not accept healthy volunteersQualifiers
Age >17 years.
Unscheduled presentation to a participating emergency department with hyperglycemia (serum glucose >250 mg/dL) and significant ketonemia consistent with DKA, defined as laboratory serum/plasma β-hydroxybutyrate (BHB) >20 mg/dL (≈≥1.9 mmol/L).
Clinical phenotype consistent with ketosis-prone type 2 diabetes (no known prior diagnosis of type 1 diabetes).
Able to provide written informed consent and comply with study procedures in the ED.
Disqualifiers
Current renal replacement therapy for chronic kidney disease (hemodialysis or peritoneal dialysis).
Known history of type 1 diabetes mellitus or known GAD65 autoantibody positivity.
Diagnosed cirrhosis/advanced chronic liver disease.
Pregnancy (known pregnancy or positive test at screening).
Trial design
Design model
Parallel
Treatments tested in this trial
Arginine hydrochloride
DrugSingle intravenous infusion of arginine hydrochloride 30 g in 300 mL 10% solution (R-Gene® 10), administered over 30 minutes via infusion pump. Given as early as feasible after recognition of DKA and in addition to standard DKA care (fluids, insulin, electrolytes) at the treating clinician's discretion. Investigational pharmacy prepares and dispenses blinded study drug; containers are covered to mask appearance and infusion parameters match placebo. Continuous safety monitoring with prespecified stop criteria. Study blood draws at 0 (pre-infusion), 10, 30, and 90 minutes for C-peptide/glucose and amino acids; clinical labs track β-hydroxybutyrate clearance and total insulin over 24 hours.
Sodium Chloride 0.9%
DrugPlacebo comparator: 0.9% sodium chloride administered as a single 30-minute intravenous infusion using identical tubing, pump settings, and covered container as the active arm to preserve blinding. Initiated as early as feasible after recognition of DKA and provided in addition to standard DKA care at the treating clinician's discretion. Study assessments occur on the same schedule as the active arm (0, 10, 30, and 90 minutes) with continuous safety monitoring during and after infusion and follow-up through 90 days.
Treatment groups
60 Participants
are divided into 2 treatment groupsGroup A: Arginine Hydrochloride 30 g IV + Standard DKA CareActive comparator 1 intervention
Group B: Placebo (0.9% Saline) IV + Standard DKA CarePlacebo comparator 1 intervention
Trial outcomes
Primary outcomes
1
Change in endogenous insulin secretion (C-peptide/glucose ratio)
Serum C-peptide (ng/mL) and plasma glucose (mg/dL) will be measured at 0 (pre-infusion), 10, 30, and 90 minutes from infusion start. The C-peptide/glucose ratio will be calculated at each time. Primary summary = change from baseline to 90 minutes (90-min ratio minus baseline ratio). Higher values indicate greater recruitable endogenous insulin secretion.
Time frame
Baseline (pre-infusion) to 90 minutes after infusion startSecondary outcomes
1
Change in beta-hydroxybutyrate (BHB) concentration
Difference in serum BHB from baseline to 24 hours (baseline BHB minus 24-hour BHB). Positive values reflect ketone clearance.
Time frame
Baseline to 24 hours2
Rate of BHB clearance
Slope of BHB concentration over time using all clinically obtained values in the first 24 hours.
Time frame
0-24 hours3
Total insulin administered in first 24 hours
Sum of all insulin doses (IV and/or subcutaneous) administered as part of routine care.
Time frame
0-24 hours4
Plasma arginine concentration (change from baseline)
HPLC-based quantification of plasma arginine at baseline and 90 minutes; change = 90-min minus baseline.
Time frame
Baseline to 90 minutesOther outcomes
1
Platelet mitochondrial complex IV activity (change from baseline)
Enzymatic activity of cytochrome c oxidase (complex IV) measured in isolated platelet-rich plasma; normalized to protein content or citrate synthase as per lab SOP; change = 90-min minus baseline.
Time frame
Baseline to 90 minutes2
Platelet mitochondrial complex V (ATP synthase) activity (change from baseline)
Activity measured in isolated platelets; normalized per lab SOP; change = 90-min minus baseline.
Time frame
Baseline to 90 minutesSponsors and contacts
Click on the lead sponsor to view all of their trials.
David K Carroll
Lead sponsor
Wayne State University
Sponsor institution
Wayne State University
Collaborator
Detroit Medical Center
Collaborator
Source ClinicalTrials.gov