Clinical trial NCT03278730: Efficacy of Para-Tyrosine Supplementation on the Survival and Clinical Outcome in Patients With Sepsis
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
Study type: INTERVENTIONAL
Overall status: SUSPENDED
Phase: PHASE2
Conditions: Sepsis
Keywords: sepsis
para-Tyrosine
ortho-Tyrosine
meta-Tyrosine
Lead sponsor: University of Pecs
Sponsor class: OTHER
First posted: 2017-09-12
Enrollment: 296
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: The objective is to evaluate, whether p-Tyr supplementation reduces the ICU mortality of the patients with sepsis comparing to placebo group
Primary purpose: PREVENTION

Brief 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.

Detailed 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.

Eligibility criteria: 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 β-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

Primary outcomes:
measure: Mortality
timeFrame: 30 days
Secondary outcomes:
measure: Effect of para-Tyrosine supplementation on the clinical outcome of sepsis
timeFrame: 30 days
measure: Long term effects of para-Tyrosine supplementation on survival
timeFrame: 28 days
measure: Reduction in the time of ICU stay
timeFrame: 30 days
measure: Overall mortality
timeFrame: 60 days
measure: Hospitalization time
timeFrame: 60 days
measure: Safety and tolerability of para-Tyrosine supplementation (Incidence of Treatment-Emergent Adverse Events)
timeFrame: 60 days
Other outcomes:
measure: Effect of supplementation on the maintanance of the serum level of para-Tyrosine
timeFrame: 30 days
measure: Assessment of pharmacodynamics
timeFrame: 10 days
measure: Correlation of o-Tyr and m-Tyr serum levels and other parameters of inflammation
timeFrame: 10 days
Locations:
city: Pécs
country: Hungary
facility: 2nd Department of Medicine and Nephrological Center
state: Baranya
city: Pécs
country: Hungary
facility: Department of Anaesthesiology and Intensive Care
state: Baranya
Study officials:
affiliation: University of Pecs
name: István Wittmann, MD,PhD,DSc
role: PRINCIPAL_INVESTIGATOR
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