Therapeutic Strategies to Reduce Endothelial Ischemia-reperfusion Injury

NCT06825143 | Not Yet Recruiting Early Phase 1 DMC FDA Drug

• 1 other identifier: HRC-2024-02-06-R33
• Study Type: interventional
• Target: 68
• Locations: 1 country
• Sites: 1

Brief Summary

The objective of this clinical trial is to better understand how lactate, a naturally occurring energy substance, can be used to lessen damage to the vascular system in adults with a high cardiovascular disease risk. The main questions it aims to answer are:

1. 1.Does giving lactate intravenously reduce injury to the vascular system?
2. 2.Does giving lactate intravenously together with blood flow occlusion - known as ischemic preconditioning, reduce vascular injury better than blood flow occlusion by itself?
3. 3.How does lactate help the vascular system?

Conditions

Metabolic Syndrome; Vascular Injury; Ischemic Preconditioning; Endothelial Function (reactive Hyperemia); Endothelial Dysfunction

Keywords

endothelial ischemia/reperfusion injury; remote ischemic preconditioning; lactate; metabolic syndrome

Outcome Measures

Primary Outcomes (2)

• Baseline value of the mean peak forearm blood flow response to reactive hyperemia.

  Endothelium-dependent vasodilation will be assessed in the experimental (nondominant) arm by the forearm blood flow response to reactive hyperemia using strain-gauge venous occlusion plethysmography. Data are reported in ml of blood per 100 mL arm volume per minute.

  Baseline (time 0)

• Mean peak forearm blood flow response to reactive hyperemia at 3 hours.

  Endothelium-dependent vasodilation will be assessed in the experimental (nondominant) arm by the forearm blood flow response to reactive hyperemia using strain-gauge venous occlusion plethysmography. Data are reported in ml of blood per 100 mL arm volume per minute.

  At 3 hours

Study Arms (2)

Ischemic preconditioning versus intravenous lactate infusion

ACTIVE COMPARATOR

To goal of this Arm is to compare the capacity of ischemic preconditioning (IPC) to protect against endothelial ischemia/reperfusion injury to the capacity of an intravenous lactate infusion to protect against endothelial ischemia/reperfusion injury. To achieve this goal, investigators will test the hypothesis that the capacity for intravenous lactate to reduce endothelial injury will be equivalent to that of IPC. Participants will be randomized to one of two Interventions. One Intervention will be the IPC intervention which is thought to be effective in treating the condition under study. The other intervention is the intravenous lactate intervention, which is the main focus of the study.

Procedure: Ischemic preconditioning; Drug: Intravenous lactate infusion; Procedure: No ischemic preconditioning (control); Drug: Normal Saline Infusion (Placebo)

Ischemic preconditioning combined with an intravenous lactate infusion

EXPERIMENTAL

To goal of this Arm is to compare the capacity of ischemic preconditioning (IPC) combined with an intravenous lactate infusion to protect against endothelial ischemia/reperfusion injury to IPC by itself. To achieve this goal, investigators will test the hypothesis that the capacity to protect against endothelial injury will be better when IPC and lactate are combined compared to IPC alone. Participants will be randomized to one of two Interventions. One Intervention will be the IPC intervention by itself. The other intervention will be adding an intravenous lactate infusion together with IPC which is the main focus of the study.

Procedure: Ischemic preconditioning; Combination Product: Ischemic preconditioning and intravenous lactate

Interventions

Ischemic preconditioning PROCEDURE

The objective of this Intervention is to show that ischemic preconditioning (IPC) protects against endothelial ischemia/reperfusion injury. Baseline endothelium-dependent vasodilation to reactive hyperemia will be performed on the nondominant arm, followed by 3 × 5-minute cycles of IPC in the opposite arm. IPC will be induced using a blood pressure cuff placed on the opposite upper arm and inflated to 220 mmHg for 5 min, followed by 5 min of deflation. This procedure will be repeated two additional times taking about 30 minutest to complete. Following a 10-minute rest phase, endothelial injury will be induced using a blood pressure cuff that will be inflated to stop blood flow through the nondominant arm for 20 minutes, followed by 15 minutes of cuff deflation. Endothelium-dependent vasodilation measurements will be repeated immediately after the 15-minute cuff deflation phase.

Ischemic preconditioning combined with an intravenous lactate infusion; Ischemic preconditioning versus intravenous lactate infusion

Intravenous lactate infusion DRUG

The objective of this Intervention is to show that an intravenous infusion of lactate protects against endothelial ischemia/reperfusion injury. Baseline endothelium-dependent vasodilation to reactive hyperemia will be performed on the nondominant arm. Thereafter, a continuous intravenous infusion of lactate will be delivered in the contralateral arm. After systemic lactate reaches \~3 mmol/L, endothelial injury will be induced using a blood pressure cuff that will be inflated to stop blood flow through the nondominant arm for 20 minutes, followed by 15 minutes of cuff deflation. Endothelium-dependent vasodilation measurements will be repeated immediately after the 15-minute cuff deflation phase.

Ischemic preconditioning versus intravenous lactate infusion

No ischemic preconditioning (control) PROCEDURE

The objective of this Intervention is to show that a control experiment without ischemic preconditioning does not provide protection against endothelial ischemia/reperfusion injury. Baseline endothelium-dependent vasodilation to reactive hyperemia will be performed on the nondominant arm, followed by 3 × 5-minute cycles of no upper arm occlusion in the opposite arm. To avoid upper arm occlusion, a blood pressure cuff will be placed on the upper arm and inflated to a low pressure of 20 mmHg pressure to not influence blood flow through the arm. This control procedure will be repeated two additional times taking about 30 minutes to complete. Following a 10-minute rest phase, endothelial injury will be induced using a blood pressure cuff that will be inflated to stop blood flow through the nondominant arm for 20 minutes, followed by 15 minutes of cuff deflation. Endothelium-dependent vasodilation measurements will be repeated immediately after the 15-minute cuff deflation phase.

Ischemic preconditioning versus intravenous lactate infusion

Normal Saline Infusion (Placebo) DRUG

The objective of this Intervention is to show that a placebo intravenous infusion does not protect against endothelial ischemia/reperfusion injury. Baseline endothelium-dependent vasodilation to reactive hyperemia will be performed on the nondominant arm. Thereafter, a continuous infusion of normal saline that does not contain lactate will be delivered in the contralateral arm. After 20 minutes of the placebo infusion, endothelial injury will be induced using a blood pressure cuff that will be inflated to stop blood flow through the nondominant arm for 20 minutes, followed by 15 minutes of cuff deflation. Endothelium-dependent vasodilation measurements will be repeated immediately after the 15-minute cuff deflation phase.

Ischemic preconditioning versus intravenous lactate infusion

Ischemic preconditioning and intravenous lactate COMBINATION_PRODUCT

The objective of this Intervention is to show that combining ischemic preconditioning (IPC) with an intravenous infusion of lactate provides the best protection against endothelial injury. First, baseline endothelial function to reactive hyperemia will be performed on the nondominant arm. Thereafter, a continuous intravenous infusion of lactate will be delivered in the contralateral arm. After that investigators will administer IPC using a blood pressure cuff placed on the same upper arm and inflated to 220 mmHg for 5 min, followed by 5 min of deflation. This procedure will be repeated two more times taking about 30 minutes to complete. The intravenous lactate infusion will be maintained. After a 10-minute rest phase and while lactate is still being infused, endothelial injury will be induced using a blood pressure cuff inflated to stop blood flow through the opposite arm (nondominant arm) for 20 minutes, followed by 15 minutes of cuff deflation. Endothelial function will be repeated.

Ischemic preconditioning combined with an intravenous lactate infusion

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Sedentary men and women between the ages of 18-65 years of all races and ethnicity
• Diet and weight stable for the past 3 months
• Non-smoking and not using tobacco or electronic cigarettes

You may not qualify if:

• Use of medications known to affect cardiovascular function
• Hyperlactemia
• Type A lactic acidosis
• Type B lactic acidosis
• Extracellular hyperhydration or hypervolemia
• Hyperkaliemia
• Hypercalcemia
• Metabolic alkalosis
• Metabolic acidosis
• McArdle's Disease
• Diabetes Type 1 and 2
• Taking oral contraceptives or hormone replacement therapy
• Body mass index greater than or equal to 35
• Smoking or using smokeless tobacco and electronic cigarettes
• Cardiovascular, cerebrovascular, liver, respiratory, and renal disease

Sponsors & Collaborators

• Gary Van Guilder: lead

Study Sites (1)

High Altitude Physiology Laboratory at Western Colorado University

Gunnison, Colorado, 81231, United States

Location

MeSH Terms

Conditions

Metabolic Syndrome; Vascular System Injuries; Hyperemia; Reperfusion Injury

Interventions

Ischemic Preconditioning

Condition Hierarchy (Ancestors)

Insulin Resistance; Hyperinsulinism; Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Vascular Diseases; Cardiovascular Diseases; Wounds and Injuries; Postoperative Complications; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Therapeutics; Investigative Techniques

Central Study Contacts

Gary P Van Guilder, PhD

CONTACT

970-943-7133; gvanguilder@western.edu

Study Design

• Study Type: interventional
• Phase: early phase 1
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Principal Investigator

Model Details: The overall interventional study model will utilize a parallel design equivalence trial and a parallel design superiority trial. Both trials will have two Arms.

Study Record Dates

• First Submitted: January 21, 2025
• First Posted: February 13, 2025
• Study Start (Estimated): October 1, 2026
• Primary Completion (Estimated): September 30, 2029
• Study Completion (Estimated): June 30, 2030
• Last Updated: February 13, 2025

Record last verified: 2025-01

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)