Pharmacologic Induction of Tolerance for Hypoxia & Hypothermia

NCT ID: NCT06129825

Last Updated: 2025-01-28

Basic Information

• Recruitment Status: RECRUITING
• Total Enrollment: 50 participants
• Study Classification: OBSERVATIONAL
• Study Start Date: 2023-12-11
• Study Completion Date: 2026-07-30

Brief Summary

Warfighter Performance Optimization in Extreme Environments remains an area of important and intense investigation, with the following goals: (1) Optimize, sustain and augment medical readiness and physiological/ psychological performance in extreme and hazardous military operational environments and (2) develop joint DoD countermeasures and guidance to sustain performance, assess physiological status, and reduce injury risk in extreme and hazardous operational environments. Successful and safe outcomes in extreme and hazardous operational environments require that warfighters maintain optimum cognitive and exercise performance during physiologic stress. Extreme environmental conditions encountered in such environments include warfighter exposure to hypoxia and hypothermia, alone or in combination. Both hypoxia and hypothermia undermine O2 delivery system homeostasis, imposing dangerous constraints upon warfighter cognitive and exercise capacity.

While red blood cells (RBCs) are commonly recognized as O2 transport agents, their function as a key signaling and control node in O2 system delivery homeostasis is newly appreciated. Through O2 content-responsive modulation of RBC energetics, biomechanics, O2 affinity and control of vasoactive effectors in plasma - RBCs coordinate stabilizing responses of the lung, heart, vascular tree and autonomic nervous system - in a fashion that maintains O2 delivery system homeostasis in the setting of either reduced O2 availability (hypobaric hypoxia) or increased O2 demand (hypothermia). Human RBCs demonstrate adaptive responses to exercise, hypoxia and hypothermia - these changes are commonly appreciated as a key element enabling high altitude adaptation. However, under conditions of hypoxia and hypothermia, without prior adaptation, RBC performance is adversely impacted and limits the dynamic range of stress adaptation for O2 delivery homeostasis - therefore limiting warfighter exercise capacity and cognitive performance in extreme environments, such as during acute mountain sickness.

Detailed Description

The investigator's strategy is to: (a) repurpose approved drugs with potential for salutary effect upon RBC performance attributes that contribute to O2 delivery homeostasis during stress and (b) efficiently identify lead candidates through sequential evaluation in relevant and rigorous benchtop and in vivo models that include examination for gender-specific effects. Our assay platforms are selected to characterize RBC physiology relevant to O2 delivery, with focus upon RBC O2 affinity, energetics, biomechanics, vascular interaction and control of regional blood flow. The investigator will sample RBC suspensions serially (0, 1,3h) and quantify the RBC performance attributes across the range of modeled environmental extremes, defining RBC performance constraint as > 20% impairment in each attribute and determine pharmacologic rescue (defined as > 20% improvement in each attribute) using mixed model RM-ANOVA, as a function of gender. The investigator will power analysis to 80% at a<5%; based on our published data with these assays and experience, this requires 10-15 subjects/group. Drug candidates with evidence of PhIT-HyHo potential will advance to in vivo screening, prioritized by the number of RBC attributes rescued per drug. Specific description of our approach to evaluate each RBC performance attribute follows.

RBC performance attributes will be quantified under controlled conditions (Temperature: 28 - 37°C; pO2: 50 - 100 Torr, alone and in combination in our temperature-controlled thin film tonometer38 (NB temperature simulates hypothermic body temperature): (a) glycolytic flux, (b) resilience to oxidative stress, (c) deformability & aggregation, (d) O2 affinity and Bohr effect, (e) vasoactivity.

Conditions

Hypothermia; Hypoxia; Mountain Sickness

Study Design

• Observational Model Type: COHORT
• Study Time Perspective: PROSPECTIVE

Study Groups

Healthy Adult Volunteers

Healthy Adults Volunteers \>/= 18yrs of age without acute or chronic illness.

Prospective

Intervention Type: OTHER

Single arm, healthy adult volunteers for blood donation.

Interventions

Prospective

Single arm, healthy adult volunteers for blood donation.

Intervention Type: OTHER

Eligibility Criteria

Inclusion Criteria

• Subject is >/= 18years of age.
• Subject weighs a minimum of 110lbs
• Subject must be generally healthy individual

Exclusion Criteria

• Suspected or diagnosed with ongoing (chronic) or acute infection
• Pregnant
• Non-English speaking
• Ages 89 and over

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 88 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

United States Department of Defense

FED

Sponsor Role: collaborator

University of Maryland, Baltimore

OTHER

Sponsor Role: lead

Responsible Party

Allan Doctor, MD

Principal Investigator

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Allan Doctor, PhD

Role: PRINCIPAL_INVESTIGATOR

University of Maryland, Baltimore

Locations

University of Maryland Baltimore

Baltimore, Maryland, United States

Site Status: RECRUITING

Countries

United States

Central Contacts

Allan Doctor, PhD

Role: CONTACT

Adoctor@som.umaryland.edu

314-791-0297

Tobi Rowden, RN

Role: CONTACT

trowden@som.umaryland.edu

Facility Contacts

Tobi Rowden

Role: primary

410-706-6079

Other Identifiers

HP-00108068

Identifier Type: -

Identifier Source: org_study_id