Phase 1 Trial of Arginine Hydrochloride for the Management of Diabetic Ketoacidosis in Type 2 Diabetes

NCT ID: NCT07167693

Last Updated: 2025-09-11

Basic Information

• Recruitment Status: NOT_YET_RECRUITING
• Clinical Phase: PHASE1/PHASE2
• Total Enrollment: 60 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2025-11-01
• Study Completion Date: 2027-12-31

Brief Summary

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.

Detailed Description

Background and Rationale. A substantial subset of adults with type 2 diabetes develop DKA ("ketone-prone" type 2 diabetes). Many of these patients lack diabetes autoantibodies (A-) and retain recoverable β-cell function (β+). The pathophysiology appears to involve reversible β-cell dysfunction from prolonged hyperglycemia. Arginine, a cationic amino acid and physiologic insulin secretagogue, depolarizes β-cells and enhances glucose-dependent insulin release within minutes. Prior human studies show prompt rises in insulin and C-peptide after arginine in individuals with preserved β-cell reserve. Arginine may also improve nitric-oxide bioavailability and mitigate mitochondrial dysfunction-processes implicated in hyperglycemic crises. We therefore hypothesize that early intravenous arginine, added to usual DKA care, will acutely increase endogenous insulin secretion and speed clearance of ketosis without added safety concerns.

Design and Setting. Prospective, phase 1/2, randomized, double-blind, placebo-controlled, parallel-group trial at four emergency departments in the Detroit metropolitan area. Target enrollment is 60 participants (1:1 allocation).

Participants. Adults (>17 years) with hyperglycemia (generally ≥250 mg/dL) and significant ketonemia/ketosis consistent with DKA and a clinical phenotype of ketone-prone type 2 diabetes. Key exclusions include known type 1 diabetes or positive GAD65 antibodies, chronic dialysis, cirrhosis, pregnancy, allergy to arginine, or features of moderate/greater alcohol intoxication. Screening may use point-of-care capillary β-hydroxybutyrate (BHB) or breath acetone to expedite identification; confirmatory laboratory thresholds will be used per protocol.

Intervention. As early as logistics allow after recognition of DKA, participants will receive a blinded 30-minute intravenous infusion of either arginine hydrochloride 30 g in 300 mL (R-Gene® 10) or matching placebo (normal saline 500 mL). Treating teams will manage DKA per standard institutional protocols; the study does not restrict clinical care (fluids, insulin, electrolytes).

Outcomes.

Primary endpoint: Endogenous insulin secretion quantified by the C-peptide/glucose ratio at 10, 30 (end of infusion), and 90 minutes after infusion start.

Key secondary endpoints: (a) Rate of BHB decline (ketone clearance), and (b) total insulin administered in the first 24 hours.

Mechanistic/biomarker endpoints: Plasma amino acids-especially arginine, citrulline, and ornithine-to compute the Global Arginine Bioavailability Ratio (arginine/[ornithine+citrulline]) at baseline and 90 minutes; insulin, proinsulin, and diabetes autoantibodies. Exploratory endpoint: Platelet mitochondrial complex IV and V activities as markers of oxidative phosphorylation.

Safety Monitoring. Participants will be observed closely during and after infusion with serial vital signs and symptom checks (e.g., flushing, nausea, headache). Pre-specified stop criteria allow immediate interruption of the infusion. Adverse events will be assessed to 90 days (telephone/medical record review) and reported per regulatory guidance. Because of the small size and favorable safety profile of intravenous arginine, the study qualifies as early-phase with streamlined oversight; an independent Data and Safety Monitoring Board has nonetheless been chartered.

Sample Size and Analysis. Based on prior insulinotropic responses to arginine, we powered the study to detect a moderate-to-large effect (standardized mean difference ~0.8) in the primary endpoint with 80% power and α=0.05, yielding ~26 per group. Allowing for attrition, we plan to enroll 60 participants. The C-peptide/glucose ratio will be assessed for normality and compared between groups with appropriate parametric or transformed analyses; ketone clearance and insulin dose will be analyzed similarly. Prespecified sensitivity analyses will account for baseline severity and timing of insulin initiation.

Operational Notes. To facilitate early enrollment, research staff will screen patients with suspected DKA using point-of-care BHB or breath acetone while confirmatory labs are pending. Blood draws for study assays occur at baseline (pre-infusion), 10, 30, and 90 minutes, with additional clinically obtained labs used for outcomes (e.g., BHB over the first 24 hours). Platelet-rich plasma will be stored for exploratory mitochondrial testing using validated methods.

Impact. If early arginine infusion safely augments endogenous insulin and accelerates ketone clearance, this pragmatic, low-cost, readily available therapy could reduce reliance on prolonged insulin infusions, shorten ICU/ED resource use, and improve patient experience during DKA. Findings will inform the design of a larger phase 2/3 trial focused on clinical effectiveness and health-system outcomes in ketone-prone type 2 diabetes.

Conditions

Diabetes (DM); Diabetic Ketoacidosis; Ketosis Prone Diabetes; Hyperglycaemia (Diabetic)

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

Arginine Hydrochloride 30 g IV + Standard DKA Care

Single, blinded 30-minute intravenous infusion of arginine hydrochloride 30 g/300 mL (R-Gene® 10), initiated as early as feasible after recognition of DKA, in addition to standard DKA management (fluids, insulin, electrolytes) at the treating clinician's discretion. Infusion procedures are matched to placebo (covered containers; standardized pump settings) to maintain blinding. Study blood draws occur at 0 (pre-infusion), 10, 30, and 90 minutes for C-peptide/glucose and targeted amino acids; clinical labs are used to assess β-hydroxybutyrate clearance and total insulin administered in the first 24 h.

Group Type: ACTIVE_COMPARATOR

Arginine hydrochloride

Intervention Type: DRUG

Single 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.

Placebo (0.9% Saline) IV + Standard DKA Care

Single, blinded 30-minute intravenous infusion of matching placebo: 0.9% sodium chloride (normal saline) in a 500 mL container, administered at a standardized rate to mimic the active arm, plus standard DKA management directed by the treating team. Appearance and administration procedures match the arginine arm (covered containers; identical pumps/tubing) to preserve blinding. Study blood draws and assessments occur on the same schedule as the arginine arm (0, 10, 30, and 90 minutes).

Group Type: PLACEBO_COMPARATOR

Sodium Chloride 0.9%

Intervention Type: DRUG

Placebo 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.

Interventions

Arginine hydrochloride

Single 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.

Intervention Type: DRUG

Sodium Chloride 0.9%

Placebo 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.

Intervention Type: DRUG

Other Intervention Names

L-arginine hydrochloride; Arginine HCl; R-Gene 10; Arginine hydrochloride injection 10%; Normal saline

Eligibility Criteria

Inclusion Criteria

• 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).

Note: point-of-care capillary BHB ≥1.5 mmol/L and/or breath acetone ≥0.01% may be used for screening while confirmatory labs are pending; if confirmatory BHB ≤20 mg/dL, the participant is a screen failure.

• 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.

Exclusion Criteria

• 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).
• Known allergy or hypersensitivity to arginine or its components.
• Features of at least moderate acute alcohol intoxication at screening, per treating team.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Wayne State University

OTHER

Sponsor Role: collaborator

Detroit Medical Center

OTHER

Sponsor Role: collaborator

David K Carroll

OTHER

Sponsor Role: lead

Responsible Party

David K Carroll

Assistant Professor of Emergency Medicine

Responsibility Role: SPONSOR_INVESTIGATOR

Locations

Detroit Medical Center

Detroit, Michigan, United States

Countries

United States

Facility Contacts

David K Carroll, M.D.

Role: primary

hj7218@wayne.edu

6175830221

Other Identifiers

24-12-7395

Identifier Type: -

Identifier Source: org_study_id