S-Nitrosylation (SNO) Therapy During Autologous Blood Transfusion

Phase 1 Study of S-Nitrosylation Therapy to Improve Tissue Oxygenation During Autologous Blood Transfusion in Healthy Volunteer

The Purpose of the study is to test the hypothesis that administration of an S-nitrosylating (SNO) agent can improve tissue oxygenation during transfusion of packed red blood cells (RBCs).

Study Overview

• Status: Recruiting
• Conditions: Transfusion Related Complication
• Intervention / Treatment: Drug: SNO; Drug: Red Blood Cell; Drug: Normal Saline

Detailed Description

Transfusion is the most common therapeutic intervention employed to maintain and/or improve tissue and end-organ oxygen delivery. Despite the conceptual simplicity of this treatment recent studies indicate that RBC infusion often produces little clinical benefit and may actually harm the recipient by exacerbating rather than correcting anemia-induced tissue hypoxia.

The main driver/regulator of tissue oxygenation is blood flow not blood oxygen content. In turn flow into the microvasculature is controlled by small molecules called S-nitrosothiols (SNOs), the most important of which is S-nitrosylated hemoglobin (SNO-Hb).

The investigators determined that storage of human blood leads to rapid losses in SNO-Hb that are precisely paralleled by losses in the ability of stored RBCs to dilate blood vessels and thereby deliver oxygen. The investigators have now recently completed an autologous human blood transfusion that confirms the pre-clinical findings in that administration of 1 unit of packed RBCs to young healthy subjects did not improve tissue oxygenation and reduced circulating SNO-Hb levels.

This novel mechanism for the loss of physiological activity in banked blood and, more importantly, a putative intervention for its correction, raise the possibility that restoration of NO bioactivity could correct the deficit in oxygen delivery. As such, The Investigators plan to repeat our transfusion study with the addition of administering an S-nitrosylating agent during RBC infusion.

• Study Type: Interventional
• Enrollment (Estimated): 20
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: James Reynolds, PhD; Phone Number: 216-844-3267; Email: jxr343@case.edu
• Study Contact Backup: Name: Mada Helou, MD; Phone Number: 216-844-7330; Email: Mada.Helou@UHhospitals.org

Study Locations

• United States
  • Ohio
    • Cleveland, Ohio, United States, 44106
      • Recruiting
      • University Hospitals Cleveland Medical Center
      • Contact: Mada Helou, MD; Phone Number: 216-844-7330; Email: Mada.Helou@UHhospitals.org
      • Principal Investigator: Mada Helou, MD
      • Contact: James D Reynolds, PhD; Phone Number: (216) 368-5727; Email: jxr343@case.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 35 years (Adult)
• Accepts Healthy Volunteers: Yes

Description

Eligibility Criteria

Recruiting and studying of healthy human subjects with no pre-existing pathologic conditions from the local population. As a result the inclusion criteria is deliberately broad.

Inclusion Criteria

1. Hemoglobin > 12 g/dl
2. Healthy, non-pregnant adults with no pre-existing blood disorders or disease states that impact oxygen delivery.

2a. Active blood and platelet donors will be sought as study participants since these individuals are familiar with the routines for blood withdrawal and re-infusion.

Exclusion Criteria

The exclusion criteria is derived from the American Red Cross(ARC) Standard Operating Procedure (SOP) for autologous donation AND the parameters set out in the investigational new drug application (IND).

1. Individuals who are pregnant, breastfeeding, or are unwilling to avoid pregnancy during the study.
2. Individuals with an anatomic anomaly that would increase the risks associated with placement of the vascular catheters.
3. Individuals who report chronic diseases requiring medication of the heart, lungs, kidney, liver, etc or afflicted with any acute or chronic pathology that in the opinion of the screening physician makes them unsuitable for study.
4. Individuals with a recent history of antibiotic therapy (check for underlying cause).
5. Individuals unwilling to refrain from taking any phosphodiesterase 5 (PDE-5) inhibitor for at least 24 h prior to donation and/or autologous transfusion.
6. Individuals taking a vitamin K antagonist (warfarin) or other anticoagulant (e.g. heparin, clopidogrel, enoxaparin or dalteparin).
7. Individuals taking allopurinol, beta-adrenergic blockers, tricyclic antidepressants, meperidine (or related central nervous system (CNS) agents), or nitrates.
8. Individuals on long-term antihistamine therapy 8a. The study physician will determine on a case by case basis the suitability for inclusion of individuals who control seasonal or acute allergies with occasional antihistamine use.
9. Individuals with blood pressure parameters outside the normal range of 90-180 mm Hg systolic and 50-100 mm Hg diastolic.
10. Individuals with heart rates outside the range of 50 to 100 beats per minutes or with a pathologic irregularity.

10a. Pulses lower than 50 may be acceptable if the study participant participates in endurance training. The study physician will be consulted for evaluation.

11. Individuals with an inherited or acquired blood coagulation disorder, congenital methemoglobinemia, or a familial hemoglobinopathy that impacts oxygen delivery (e.g. sickle cell).

12. Individuals with any illness that may increase the risks associated with the study.

13. Individuals who previously received blood products to treat an acute condition will be evaluated on a case by case basis.

14. Individuals who report an acute or chronic disease state that may impact oxygen delivery.

15. Individuals with evidence of diminished lung capacity.

16. Individuals who might have difficulty with the placement of a face mask (e.g. claustrophobia, uncontrolled asthma, severe allergies, sensitive skin) and/or the inhalation of a product for approximately 1-2 hr.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Blood transfusion with SNO agent; Autologous blood transfusion packed red blood cells (RBCs) while inhaling S-nitrosylating agent (SNO) A single intra venous blood transfusion of one unit of packed Red Blood Cells (RBCs) will be given over the standard transfusion flow rate of 5 ml/min under the direction of a physician or a licensed medical professional. Inhalation of SNO agent, 20-40 parts per million will occur during the transfusion.	Drug: SNO; S-nitrosylating agent (SNO) Inhalation; Drug: Red Blood Cell; Blood transfusion (RBCs)
Placebo Comparator: Normal Saline with SNO agent; Normal Saline Transfusion while inhaling S-nitrosylating agent (SNO) A single intra venous infusion of one unit of normal saline, will be given over the standard transfusion flow rate of 5 ml/min under the direction of a physician or a licensed medical professional. Inhalation of the SNO agent at 20-40 parts per million, will occur during the transfusion.	Drug: SNO; S-nitrosylating agent (SNO) Inhalation; Drug: Normal Saline; Normal Saline transfusion

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Oxygenation Defined as change in arterial blood oxygenation	tested by arterial blood oxygen content difference - arterial blood gas (ABG) An ABG is a blood test that measures the acidity, or potential of hydrogen (pH), and the levels of oxygen (O2) and carbon dioxide (CO2) from an artery. The test is used to check the function of the patient's lungs and how well they are able to move oxygen and remove carbon dioxide. The aforementioned five components all have different normal values and represent different aspects of the blood gas. According to the National Institute of Health, typical normal values are: pH: 7.35-7.45 Partial pressure of oxygen (PaO2): 75 to 100 mmHg Partial pressure of carbon dioxide (PaCO2): 35-45 mmHg Bicarbonate (HCO3): 22-26 milliequivalent/Liter (mEqL) Oxygen saturation (O2 Sat): 94-100%	pre infusion and post infusion (every 3 to 6 hours, for 24 hours)
Oxygenation Defined as change in venous blood oxygenation CO2 ABG vs. VBG: VBG CO2 6mm Hg higher	tested by venous blood oxygen content difference - venous blood gas (VBG). An ABG is a blood test that measures the acidity, or pH, and the levels of oxygen (O2) and carbon dioxide (CO2) from an a vein. The test is used to check the function of the patient's lungs and how well they are able to move oxygen and remove carbon dioxide. pH ABG vs. VBG: VBG pH 0.03-0.05 lower HCO3 ABG vs. VBG: VBG HCO3 1.5-2.0 mEq/L lower CO2 ABG vs. VBG: VBG CO2 6mm Hg higher	pre infusion and post infusion (every 3 to 6 hours, for 24 h)
Increase in peripheral tissue oxygenation	tested with near infrared spectroscopy. An Infrared spectroscopy (IR spectroscopy or vibrational spectroscopy) involves the interaction of infrared radiation with matter. It covers a range of techniques, mostly based on absorption spectroscopy. As with all spectroscopic techniques, it can be used to identify and study chemicals.	continuous monitoring from start of transfusion until next morning. Approximately 24 hours

Collaborators and Investigators

• Sponsor: James Reynolds
• Collaborators: National Heart, Lung, and Blood Institute (NHLBI); Case Western Reserve University
• Investigators: Principal Investigator: Mada Helou, MD, University Hospitals Cleveland Medical Center

Publications and helpful links

General Publications

• Reynolds JD, Ahearn GS, Angelo M, Zhang J, Cobb F, Stamler JS. S-nitrosohemoglobin deficiency: a mechanism for loss of physiological activity in banked blood. Proc Natl Acad Sci U S A. 2007 Oct 23;104(43):17058-62. doi: 10.1073/pnas.0707958104. Epub 2007 Oct 11.
• Singel DJ, Stamler JS. Chemical physiology of blood flow regulation by red blood cells: the role of nitric oxide and S-nitrosohemoglobin. Annu Rev Physiol. 2005;67:99-145. doi: 10.1146/annurev.physiol.67.060603.090918.
• McMahon TJ, Ahearn GS, Moya MP, Gow AJ, Huang YC, Luchsinger BP, Nudelman R, Yan Y, Krichman AD, Bashore TM, Califf RM, Singel DJ, Piantadosi CA, Tapson VF, Stamler JS. A nitric oxide processing defect of red blood cells created by hypoxia: deficiency of S-nitrosohemoglobin in pulmonary hypertension. Proc Natl Acad Sci U S A. 2005 Oct 11;102(41):14801-6. doi: 10.1073/pnas.0506957102. Epub 2005 Oct 3.
• Pawloski JR, Hess DT, Stamler JS. Export by red blood cells of nitric oxide bioactivity. Nature. 2001 Feb 1;409(6820):622-6. doi: 10.1038/35054560.
• VALTIS DJ. Defective gas-transport function of stored red blood-cells. Lancet. 1954 Jan 16;266(6803):119-24. doi: 10.1016/s0140-6736(54)90978-2. No abstract available.
• Bunn HF, May MH, Kocholaty WF, Shields CE. Hemoglobin function in stored blood. J Clin Invest. 1969 Feb;48(2):311-21. doi: 10.1172/JCI105987.
• Sugerman HJ, Davidson DT, Vibul S, Delivoria-Papadopoulos M, Miller LD, Oski FA. The basis of defective oxygen delivery from stored blood. Surg Gynecol Obstet. 1970 Oct;131(4):733-41. No abstract available.
• Shah DM, Gottlieb ME, Rahm RL, Stratton HH, Barie PS, Paloski WH, Newell JC. Failure of red blood cell transfusion to increase oxygen transport or mixed venous PO2 in injured patients. J Trauma. 1982 Sep;22(9):741-6. doi: 10.1097/00005373-198209000-00004.
• Rao SV, Jollis JG, Harrington RA, Granger CB, Newby LK, Armstrong PW, Moliterno DJ, Lindblad L, Pieper K, Topol EJ, Stamler JS, Califf RM. Relationship of blood transfusion and clinical outcomes in patients with acute coronary syndromes. JAMA. 2004 Oct 6;292(13):1555-62. doi: 10.1001/jama.292.13.1555.
• Vincent JL, Baron JF, Reinhart K, Gattinoni L, Thijs L, Webb A, Meier-Hellmann A, Nollet G, Peres-Bota D; ABC (Anemia and Blood Transfusion in Critical Care) Investigators. Anemia and blood transfusion in critically ill patients. JAMA. 2002 Sep 25;288(12):1499-507. doi: 10.1001/jama.288.12.1499.
• Malone DL, Dunne J, Tracy JK, Putnam AT, Scalea TM, Napolitano LM. Blood transfusion, independent of shock severity, is associated with worse outcome in trauma. J Trauma. 2003 May;54(5):898-905; discussion 905-7. doi: 10.1097/01.TA.0000060261.10597.5C.

Study record dates

Study Major Dates

• Study Start (Actual): July 25, 2019
• Primary Completion (Estimated): July 1, 2025
• Study Completion (Estimated): July 1, 2025

Study Registration Dates

• First Submitted: June 20, 2019
• First Submitted That Met QC Criteria: June 25, 2019
• First Posted (Actual): June 26, 2019

Study Record Updates

• Last Update Posted (Actual): March 15, 2024
• Last Update Submitted That Met QC Criteria: March 13, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Keywords: Tissue Oxygenation; S-Nitrosylation; Anemia-induced tissue hypoxia; Red blood cell Transfusion
• Other Study ID Numbers: STUDY20221492; 5R01HL126900 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: All of the individual participant data collected during the trial, after deidentification and analysis will be shared.
• IPD Sharing Time Frame: Available Immediately following publication
• IPD Sharing Access Criteria: Investigators whose proposed use of the data has been approved by an independent review committee ("learned intermediary") identified for this purpose.
• IPD Sharing Supporting Information Type: SAP; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No