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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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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

Conditions
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Sepsis

Intervention / Treatment
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* Drug: Para-Tyrosine supplementation
* Drug: Placebo solution


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subjects must meet the following inclusion criteria to be eligible for the study: Are able to provide written informed consent (either the patient or the person entitled by legislation to consent on behalf of the patient) Male and female patients ≥ 18 years 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 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: Females who are pregnant (positive β-hCG test at screening) or breastfeeding chronic use of steroids or immunosuppressive drugs within the past 3 months other therapy influencing the immune system within the past 3 months (radiotherapy, chemotherapy etc.) malignant hematologic disease jejunal tube feeding 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.) 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) Hypersensitivity to any of the excipients of the study product Known to be human immunodeficiency virus (HIV) positive Active viral hepatitis (B or C) as demonstrated by positive serology History of drug or alcohol dependency or abuse within approximately the last 2 years

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: The objective is to evaluate, whether p-Tyr supplementation reduces the ICU mortality of the patients with sepsis comparing to placebo group
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Para-Tyrosine intervention<br>The patients will receive the study drug during their stay at the ICU but for a maximum of 7 days. Study drug will be dispensed by a nominated member of the study team and administered to the patients by the ICU staff via nasogastric tube in form of oral suspension. The content of the hard capsules will be dissolved in 20 ml of tap water before the dosing. Drug name: Tyrosine. Strength 500 mg. Oral dose form: hard capsule. Number of Dispensed at frequency of 3x2 g daily. Duration of administration: 4 to 7 days. | Drug: Para-Tyrosine supplementation<br>* 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.<br>|
| Placebo Comparator: Placebo<br>The patients will receive the study drug during their stay at the ICU but for a maximum of 7 days. Study drug will be dispensed by a nominated member of the study team and administered to the patients by the ICU staff via nasogastric tube in form of oral suspension. The content of the hard capsules will be dissolved in 20 ml of tap water before the dosing. Drug name: Placebo.. Strength N/A. Oral dose form: capsule matching to Tyrosine capsule. Number of Dispnsed an frequency 3x2 g daily. Duration of administration: 4 to 7 days. | Drug: Placebo solution<br>* 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.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 
| 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 | 
| Reduction in the time of ICU stay | The investigators shall evaluate, whether the treatment can reduce the time of the ICU stay | 30 days | 
| Overall mortality | The investigators will evaluate the effect on overall mortality of patients with sepsis during their hospitalization | 60 days | 
| Hospitalization time | The investigators will evaluate the effect of p-Tyr supplemetation on the overall hospitalization time | 60 days | 
| 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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sepsis, para-Tyrosine, ortho-Tyrosine, meta-Tyrosine