Phase 1 Randomized Clinical Trial of Arginine Hydrochloride Administration to Reduce Duration of Diabetic Ketoacidosis in Patients With Type 2 Diabetes
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 发起方
- 入组人数
- 60
- 试验地点
- 1
- 主要终点
- Change in endogenous insulin secretion (C-peptide/glucose ratio)
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
盲法说明
Quadruple-blind with centralized 1:1 allocation concealment. A site research pharmacist (unblinded) prepares study drug; infusion containers are covered to mask volume/appearance and both arms are run over 30 minutes using identical pump settings. Participants, bedside clinicians, investigators, and outcomes assessors remain blinded through database lock. Emergency unblinding is permitted for medical necessity via pharmacy access to allocation codes; all unblindings are logged. Laboratory personnel analyze specimens using coded IDs.
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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.
排除标准
- •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.
研究组 & 干预措施
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.
干预措施: Arginine hydrochloride (Drug)
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).
干预措施: Sodium Chloride 0.9% (Drug)
结局指标
主要结局
Change in endogenous insulin secretion (C-peptide/glucose ratio)
时间窗: Baseline (pre-infusion) to 90 minutes after infusion start
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.
次要结局
- Change in beta-hydroxybutyrate (BHB) concentration(Baseline to 24 hours)
- Rate of BHB clearance(0-24 hours)
- Total insulin administered in first 24 hours(0-24 hours)
- Plasma arginine concentration (change from baseline)(Baseline to 90 minutes)
- Global Arginine Bioavailability Ratio (GABR)(Baseline to 90 minutes)
研究者
David K Carroll
Assistant Professor of Emergency Medicine
Wayne State University