Clinical trial NCT03999229: S-Nitrosylation (SNO) Therapy During Autologous Blood Transfusion
Official title: Phase 1 Study of S-Nitrosylation Therapy to Improve Tissue Oxygenation During Autologous Blood Transfusion in Healthy Volunteer
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
Conditions: Transfusion Related Complication
Keywords: S-Nitrosylation
Tissue Oxygenation
Anemia-induced tissue hypoxia
Red blood cell Transfusion
Lead sponsor: Case Western Reserve University
Sponsor class: OTHER
Collaborators: name: Case Western Reserve University
name: National Heart, Lung, and Blood Institute (NHLBI)
First posted: 2019-06-26
Enrollment: 35
Sex: ALL
Minimum age (years): 18
Maximum age (years): 35
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: This is an open-label phase I trial. Healthy young adult volunteers that would considered eligible by American Red Cross standards to donate blood will be screened by qualified practitioners for eligibility to participate in the above mentioned study. We anticipate an accrual number of 35, with subjects randomized to receive their blood (n=30) or saline (n=5) while breathing an SNO agent.
Primary purpose: TREATMENT

Brief summary: 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).

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.

Eligibility criteria: 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, i.e., higher than 130 mm Hg systolic and/or higher than 90 mm Hg diastolic; mild hypertension is acceptable by the Red Cross for blood donation.
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 2-3 hours.

Primary outcomes:
measure: Peripheral Tissue Oxygenation
timeFrame: Monitoring is continuous once the probes are placed on the skin. It will start approximately 30 minutes prior to blood transfsuion and continue overnight and then stopped next morning when subject is discharged. Total time is up to 24 hours.
measure: Oxygen Utilization
timeFrame: Blood samples are obtained every 3 to 6 hours before during and after blood transfsuion until subject is discharged Total time is up to 24 hour
Secondary outcomes:
measure: Kidney Function Test
timeFrame: Blood samples are obtained every 3 to 6 hours before during and after blood transfsuion until subject is discharged Total time is up to 24 hour
measure: Liver Function Test
timeFrame: Blood samples are obtained every 3 to 6 hours before during and after blood transfsuion until subject is discharged Total time is up to 24 hour
measure: Assessment of Immune Status
timeFrame: Blood samples are obtained every 3 to 6 hours before during and after blood transfsuion until subject is discharged Total time is up to 24 hour
Other outcomes:
Locations:
city: Cleveland
country: United States
facility: University Hospitals Cleveland Medical Center
state: Ohio
Study officials:
affiliation: University Hospitals Cleveland Medical Center
name: Mada Helou, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Case Western Reserve University
name: Batuhan Degis, MD
role: STUDY_DIRECTOR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.