Efficacy of Para-Tyrosine Supplementation on the Survival and Clinical Outcome in Patients With Sepsis

Sepsis Clinical Trial

Official title:

Phase 2 Single Center, Randomized, Placebo-controlled, Double-blind, Parallel Group Study to Evaluate Efficacy of Para-Tyrosine Supplementation on the Survival and Clinical Outcome in Patients With Sepsis

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT03278730
• Other study ID #: PTE-2015-02
• Status: Not yet recruiting
• Phase: Phase 2
• Start date: February 2025
• Est. completion date: February 28, 2027

Study information

• Verified date: November 2023
• Source: University of Pecs
• Contact: István Wittmann, MD,PhD,DSc
• Phone: +3672536050
• Email: istvan.wittmann[@]aok.pte.hu
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Meta-and ortho-Tyrosine are known markers of oxidative stress, while the physiological isomer, para-Tyrosine is suggested the antagonize the effects of meta- and ortho-Tyrosine. The changes in the serum levels of meta- and ortho-Tyrosine have been found to be paralel to that of the common sepsis markers. The hypothesis of the study is, that supplementation of para-Tyrosine (p-Tyr) in the early phase of sepsis may diminish some specific inflammatory procedures and thus may have a favourable impact on the disease progress, and consequently on the mortality.

Description:

Data suggest, that among the amino acids, the meta- and ortho- isomers of tyrosine are potential markers of oxydative stress. The changes in their serum levels (and urinary excretion) in sepsis were found to be parallel to the changes of the common inflammatory markers, i.e. C-reactive protein (CRP) and pro-calcitonin (PCT). However, para-Tyrosine, which is the isomer physiologically present, seemed to have different kinetics. Furthermore, according to the observations, pathological processes linked to the inflammation could be attenuated or partially or completely reversed by para-tyrosine. The hypothesis of the study is, that supplementation of para-Tyrosine (p-Tyr) in the early phase of sepsis may diminish some specific inflammatory procedures and thus may have a favourable impact on the disease progress, and consequently on the mortality. The primary objective of the study is to evaluate, whether oral P-Tyr supplementation reduces mortality compared to placebo group during the ICU stay in patients with sepsis. The primary endpoint is the comparison of mortality starting from randomization and start of treatment (which should be on the same day) during the period of ICU stay between the active treatment group and placebo group. The secondary objectives of the study are: to evaluate whether supplementation of p-Tyr has effect on clinical outcome of sepsis compared to placebo in patients receiving appropriate standard care; to evaluate the effect of p-Tyr supplementation on 28-day survival of patients with sepsis; to evaluate, whether the treatment can reduce the time of the ICU stay, to evaluate the effect on overall mortality of patients with sepsis during their hospitalization, to evaluate the effect of p-Tyr supplemetation on the overall hospitalization time, to evaluate the safety of the investigational product. The investigators wish to explore To explore whether serum level of p-Tyr can be maintained with the oral supplementation; dynamics and interrelation of the levels of oxidative stress markers (o- and m-Tyr) and the physiologic isomer of Tyr (p-Tyr) and Phenylalanine (Phe) and the correlation of o-Tyr and m-Tyr serum levels and other parameters of inflammation.

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 296
• Est. completion date: February 28, 2027
• Est. primary completion date: February 1, 2026
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

Subjects must meet the following inclusion criteria to be eligible for the study:

1. Are able to provide written informed consent (either the patient or the person entitled by legislation to consent on behalf of the patient)

2. Male and female patients = 18 years

3. Have a current primary diagnosis of sepsis based on the the third international consensus definitions for sepsis and septic shock (Sepsis-3)Willing and able to comply with all aspects of the protocol

4. Females of childbearing potential must have negtive serum pregnancy test az screening. (All females will be considered to be of childbearing potential unless they are postmenopausal i.e. amenorrheic for at least 12 consecutive months, in the appropriate age group and without other known or suspected cause or have been sterilized surgically i.e. bilateral tubal ligation, total hysterectomy, or bilateral oophorectomy, all with surgery at least 1 month before dosing) Exclusion Criteria:

Subjects must not have any of the following criteria to be eligible for the study:

1. Females who are pregnant (positive ß-hCG test at screening) or breastfeeding

2. chronic use of steroids or immunosuppressive drugs within the past 3 months

3. other therapy influencing the immune system within the past 3 months (radiotherapy, chemotherapy etc.)

4. malignant hematologic disease

5. jejunal tube feeding

6. any other significant illness in the medical history ongoing in the preceeding 1 month, which may have an influence on the survival and clinical outcome of the patients (e.g severe chronic heart failure NYHA III-IV., AMI, stroke, major surgery, COPD, renal failure, hepatic failure, hepatic cirrhosis etc.)

7. Life expectancy less, than 1 months according to the judgement of the Investigator (even without significant illness, due to age or general status of the patient)

8. Hypersensitivity to any of the excipients of the study product

9. Known to be human immunodeficiency virus (HIV) positive

10. Active viral hepatitis (B or C) as demonstrated by positive serology

11. History of drug or alcohol dependency or abuse within approximately the last 2 years

Related Conditions & MeSH terms

• Sepsis
• Toxemia

Intervention

Drug:
• Para-Tyrosine supplementation
Patients will recieve the study drug during their stay at the ICU, but for a maximum of 7 days. The study drug is 3x2 gramms of para-Tyrosine, which will be dispensed and administered in a form of oral suspension via a nasogastric tube.
• Placebo solution
Patients will recieveplacebo during their stay at the ICU, but for a maximum of 7 days. The study drug is 3x2 gramms of placebo, which will be dispensed and administered in a form of oral suspension via a nasogastric tube.

Locations

Country	Name	City	State
Hungary	2nd Department of Medicine and Nephrological Center	Pécs	Baranya
Hungary	Department of Anaesthesiology and Intensive Care	Pécs	Baranya

Sponsors (1)

Lead Sponsor	Collaborator
University of Pecs

Country where clinical trial is conducted

Hungary, 

References & Publications (25)

Bernard GR, Wheeler AP, Russell JA, Schein R, Summer WR, Steinberg KP, Fulkerson WJ, Wright PE, Christman BW, Dupont WD, Higgins SB, Swindell BB. The effects of ibuprofen on the physiology and survival of patients with sepsis. The Ibuprofen in Sepsis Study Group. N Engl J Med. 1997 Mar 27;336(13):912-8. doi: 10.1056/NEJM199703273361303. — View Citation

Bone RC, Balk RA, Cerra FB, Dellinger RP, Fein AM, Knaus WA, Schein RM, Sibbald WJ. Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. The ACCP/SCCM Consensus Conference Committee. American College of Chest Physicians/Society of Critical Care Medicine. Chest. 1992 Jun;101(6):1644-55. doi: 10.1378/chest.101.6.1644. — View Citation

Brasnyo P, Molnar GA, Mohas M, Marko L, Laczy B, Cseh J, Mikolas E, Szijarto IA, Merei A, Halmai R, Meszaros LG, Sumegi B, Wittmann I. Resveratrol improves insulin sensitivity, reduces oxidative stress and activates the Akt pathway in type 2 diabetic patients. Br J Nutr. 2011 Aug;106(3):383-9. doi: 10.1017/S0007114511000316. Epub 2011 Mar 9. — View Citation

Dandona P, Mohanty P, Hamouda W, Ghanim H, Aljada A, Garg R, Kumar V. Inhibitory effect of a two day fast on reactive oxygen species (ROS) generation by leucocytes and plasma ortho-tyrosine and meta-tyrosine concentrations. J Clin Endocrinol Metab. 2001 Jun;86(6):2899-902. doi: 10.1210/jcem.86.6.7745. — View Citation

Dellinger RP, Levy MM, Rhodes A, Annane D, Gerlach H, Opal SM, Sevransky JE, Sprung CL, Douglas IS, Jaeschke R, Osborn TM, Nunnally ME, Townsend SR, Reinhart K, Kleinpell RM, Angus DC, Deutschman CS, Machado FR, Rubenfeld GD, Webb S, Beale RJ, Vincent JL, Moreno R; Surviving Sepsis Campaign Guidelines Committee including The Pediatric Subgroup. Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock, 2012. Intensive Care Med. 2013 Feb;39(2):165-228. doi: 10.1007/s00134-012-2769-8. Epub 2013 Jan 30. — View Citation

Druml W, Heinzel G, Kleinberger G. Amino acid kinetics in patients with sepsis. Am J Clin Nutr. 2001 May;73(5):908-13. doi: 10.1093/ajcn/73.5.908. — View Citation

Hirose T, Shimizu K, Ogura H, Tasaki O, Hamasaki T, Yamano S, Ohnishi M, Kuwagata Y, Shimazu T. Altered balance of the aminogram in patients with sepsis - the relation to mortality. Clin Nutr. 2014 Feb;33(1):179-82. doi: 10.1016/j.clnu.2013.11.017. Epub 2013 Dec 14. — View Citation

Jensen GL, Miller RH, Talabiska DG, Fish J, Gianferante L. A double-blind, prospective, randomized study of glutamine-enriched compared with standard peptide-based feeding in critically ill patients. Am J Clin Nutr. 1996 Oct;64(4):615-21. doi: 10.1093/ajcn/64.4.615. — View Citation

Jorres RA, Holz O, Zachgo W, Timm P, Koschyk S, Muller B, Grimminger F, Seeger W, Kelly FJ, Dunster C, Frischer T, Lubec G, Waschewski M, Niendorf A, Magnussen H. The effect of repeated ozone exposures on inflammatory markers in bronchoalveolar lavage fluid and mucosal biopsies. Am J Respir Crit Care Med. 2000 Jun;161(6):1855-61. doi: 10.1164/ajrccm.161.6.9908102. — View Citation

Kun S, Mikolas E, Molnar GA, Selley E, Laczy B, Csiky B, Kovacs T, Wittmann I. Association of plasma ortho-tyrosine/para-tyrosine ratio with responsiveness of erythropoiesis-stimulating agent in dialyzed patients. Redox Rep. 2014 Sep;19(5):190-8. doi: 10.1179/1351000214Y.0000000090. Epub 2014 Apr 3. — View Citation

Kun S, Molnar GA, Selley E, Szelig L, Bogar L, Csontos C, Miseta A, Wittmann I. Insulin Therapy of Nondiabetic Septic Patients Is Predicted by para-Tyrosine/Phenylalanine Ratio and by Hydroxyl Radical-Derived Products of Phenylalanine. Oxid Med Cell Longev. 2015;2015:839748. doi: 10.1155/2015/839748. Epub 2015 Oct 20. — View Citation

Liebau F, Sundstrom M, van Loon LJ, Wernerman J, Rooyackers O. Short-term amino acid infusion improves protein balance in critically ill patients. Crit Care. 2015 Mar 12;19(1):106. doi: 10.1186/s13054-015-0844-6. — View Citation

Lubec B, Hayn M, Denk W, Bauer G. Brain lipid peroxidation and hydroxy radical attack following the intravenous infusion of hydrogen peroxide in an infant. Free Radic Biol Med. 1996;21(2):219-23. doi: 10.1016/0891-5849(96)00018-4. — View Citation

Mikolas E, Kun S, Laczy B, Molnar GA, Selley E, Koszegi T, Wittmann I. Incorporation of ortho- and meta-tyrosine into cellular proteins leads to erythropoietin-resistance in an erythroid cell line. Kidney Blood Press Res. 2013;38(2-3):217-25. doi: 10.1159/000355770. Epub 2014 Apr 9. — View Citation

Molnar GA, Kun S, Selley E, Kertesz M, Szelig L, Csontos C, Boddi K, Bogar L, Miseta A, Wittmann I. Role of Tyrosine Isomers in Acute and Chronic Diseases Leading to Oxidative Stress - A Review. Curr Med Chem. 2016;23(7):667-85. doi: 10.2174/0929867323666160119094516. — View Citation

Molnar GA, Mikolas EZ, Szijarto IA, Kun S, Selley E, Wittmann I. Tyrosine isomers and hormonal signaling: A possible role for the hydroxyl free radical in insulin resistance. World J Diabetes. 2015 Apr 15;6(3):500-7. doi: 10.4239/wjd.v6.i3.500. — View Citation

Molnar GA, Nemes V, Biro Z, Ludany A, Wagner Z, Wittmann I. Accumulation of the hydroxyl free radical markers meta-, ortho-tyrosine and DOPA in cataractous lenses is accompanied by a lower protein and phenylalanine content of the water-soluble phase. Free Radic Res. 2005 Dec;39(12):1359-66. doi: 10.1080/10715760500307107. — View Citation

Molnar GA, Wagner Z, Marko L, Ko Szegi T, Mohas M, Kocsis B, Matus Z, Wagner L, Tamasko M, Mazak I, Laczy B, Nagy J, Wittmann I. Urinary ortho-tyrosine excretion in diabetes mellitus and renal failure: evidence for hydroxyl radical production. Kidney Int. 2005 Nov;68(5):2281-7. doi: 10.1111/j.1523-1755.2005.00687.x. — View Citation

Pandharipande PP, Morandi A, Adams JR, Girard TD, Thompson JL, Shintani AK, Ely EW. Plasma tryptophan and tyrosine levels are independent risk factors for delirium in critically ill patients. Intensive Care Med. 2009 Nov;35(11):1886-92. doi: 10.1007/s00134-009-1573-6. Epub 2009 Jul 9. — View Citation

Ruggiero RA, Bruzzo J, Chiarella P, Bustuoabad OD, Meiss RP, Pasqualini CD. Concomitant tumor resistance: the role of tyrosine isomers in the mechanisms of metastases control. Cancer Res. 2012 Mar 1;72(5):1043-50. doi: 10.1158/0008-5472.CAN-11-2964. Epub 2012 Feb 7. — View Citation

Ruggiero RA, Bruzzo J, Chiarella P, di Gianni P, Isturiz MA, Linskens S, Speziale N, Meiss RP, Bustuoabad OD, Pasqualini CD. Tyrosine isomers mediate the classical phenomenon of concomitant tumor resistance. Cancer Res. 2011 Nov 15;71(22):7113-24. doi: 10.1158/0008-5472.CAN-11-0581. — View Citation

Selley E, Kun S, Kurthy M, Kovacs T, Wittmann I, Molnar GA. Para-Tyrosine Supplementation Improves Insulin- and Liraglutide- Induced Vasorelaxation in Cholesterol-Fed Rats. Protein Pept Lett. 2015;22(8):736-42. doi: 10.2174/0929866522666150610093039. — View Citation

Shaw JH, Wildbore M, Wolfe RR. Whole body protein kinetics in severely septic patients. The response to glucose infusion and total parenteral nutrition. Ann Surg. 1987 Mar;205(3):288-94. doi: 10.1097/00000658-198703000-00012. — View Citation

Singer M, Deutschman CS, Seymour CW, Shankar-Hari M, Annane D, Bauer M, Bellomo R, Bernard GR, Chiche JD, Coopersmith CM, Hotchkiss RS, Levy MM, Marshall JC, Martin GS, Opal SM, Rubenfeld GD, van der Poll T, Vincent JL, Angus DC. The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA. 2016 Feb 23;315(8):801-10. doi: 10.1001/jama.2016.0287. — View Citation

Szijarto IA, Molnar GA, Mikolas E, Fisi V, Cseh J, Laczy B, Kovacs T, Boddi K, Takatsy A, Gollasch M, Koller A, Wittmann I. Elevated vascular level of ortho-tyrosine contributes to the impairment of insulin-induced arterial relaxation. Horm Metab Res. 2014 Oct;46(11):749-52. doi: 10.1055/s-0034-1387701. Epub 2014 Sep 10. — View Citation

* Note: There are 25 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Effect of supplementation on the maintanance of the serum level of para-Tyrosine	The investigators will explore using high performance liquid cromatography (HPLC) whether serum level of p-Tyr can be maintained with the oral supplementation	30 days
Other	Assessment of pharmacodynamics	Exploration of the dynamics and interrelation of the levels of oxidative stress markers (o- and m-Tyr) and the physiologic isomer of Tyr (p-Tyr) and Phenylalanine (Phe)	10 days
Other	Correlation of o-Tyr and m-Tyr serum levels and other parameters of inflammation	The investigators will assess the correlation of o-Tyr and m-Tyr serum levels and other parameters of inflammation	10 days
Primary	Mortality	Comparison of mortality starting from randomization and start of treatment (which should be on the same day) during the period of ICU stay between the active treatment group and placebo group.	30 days
Secondary	Effect of para-Tyrosine supplementation on the clinical outcome of sepsis	The investigators wish to evaluate whether supplementation of p-Tyr has effect on clinical outcome (appearance of organ failures due to sepsis: renal failure, respiratory failure, coagulation disorders, hepatic failure, cardiac failure, need for vasopressors, CH balance, nitrogen-balance) of sepsis compared to placebo in patients receiving appropriate standard care. The investigators wish to assess wether para-Tyrosine supplementation can ameliroate the time course and severity of sepsis	30 days
Secondary	Long term effects of para-Tyrosine supplementation on survival	The investigators would like to evaluate the effect of p-Tyr supplementation on 28-day survival of patients with sepsis based on the patients' electronic documentation	28 days
Secondary	Reduction in the time of ICU stay	The investigators shall evaluate, whether the treatment can reduce the time of the ICU stay	30 days
Secondary	Overall mortality	The investigators will evaluate the effect on overall mortality of patients with sepsis during their hospitalization	60 days
Secondary	Hospitalization time	The investigators will evaluate the effect of p-Tyr supplemetation on the overall hospitalization time	60 days
Secondary	Safety and tolerability of para-Tyrosine supplementation (Incidence of Treatment-Emergent Adverse Events)	The investigators wish to evaluate the safety of the investigational product: Treatment-Emergent Adverse Events and Treatment-Emergent Serious Adverse Events shall be recorded, using physiological parameters such as impairment in renal and hepatic function, bone marrow toxicity, severe blood pressure changes, tachycardia etc.	60 days