Efficacy and Safety of Rheosorbilact® Solution for Infusion, in a Complex Therapy of Burns

Burns Clinical Trial

Official title:

Open-label, Randomized, Controlled, With Blind Assessor, Study to Assess Efficacy and Safety of Rheosorbilact®, Solution for Infusion ("Yuria-Pharm"), in Comparison With Ringer's Lactate,Solution for Infusion, in a Complex Therapy of Burns

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04152096
• Other study ID #: RheoSTAT-CP0669
• Status: Recruiting
• Phase: Phase 4
• Start date: January 24, 2017
• Est. completion date: March 30, 2021

Study information

• Verified date: November 2019
• Source: Yuria-Pharm
• Contact: Viktoriia Viktoriia Osiichuk
• Phone: 503417129
• Email: viktoriia.osiichuk[@]uf.ua
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This study evaluates the efficacy and safety of Rheosorbilact®, solution for infusion ("Yuria-Pharm" LLC), in comparison with Ringer's Lactate, solution for infusion, in a complex therapy of burns. Half of participants will receive Rheosorbilact® in complex therapy, while the other half will receive Ringer's Lactate in complex therapy.

Description:

Rheosorbilact® has rheological, anti-shock, detoxification, and alkalizing effects. Sorbitol and sodium lactate are the major pharmacologically active ingredients. In the liver, sorbitol is first converted into fructose, which is then converted into glucose, and then into glycogen. Part of sorbitol is used for urgent energy needs, while the other part is kept as a reserve in the form of glycogen. Isotonic sorbitol solution has a disaggregating effect and, therefore, improves microcirculation and tissue perfusion.

The management of metabolic acidosis with sodium lactate goes more slowly compared to bicarbonate solution, as far as sodium lactate enters the metabolic process; however the latter does not cause swings in pH values. The effect of sodium lactate is typically seen 20 to 30 minutes after administration.

Sodium chloride is a plasma-substituting agent that exhibits a detoxification and rehydration effect. It replenishes the deficiency of sodium and chlorine ions in various pathological conditions.

Calcium chloride replenishes deficiency of calcium ions. Calcium ions are essential in the transmission of nerve impulses, contraction of skeletal and smooth muscles, myocardial activity, bone tissue formation, and blood clotting. It reduces the permeability of cells and vascular walls, prevents the development of inflammatory reactions, enhances the resistance of the body to infections and can significantly boost phagocytosis.

Potassium chloride restores the water-electrolyte balance. It exhibits a negative chrono- and bathmotropic action and, when administered in high doses, has a negative ino- and dromotropic and moderate diuretic effect. It is involved in the process of nerve impulse conduction, increases the content of acetylcholine and causes excitation of the sympathetic segment of the autonomic nervous system and improves the contraction of skeletal muscles in subjects with muscular dystrophy or myasthenia.

Rheosorbilact® is administered to improve capillary blood flow for the prevention and treatment of traumatic, surgical, hemolytic, toxic and burn shock, acute blood loss, and burn disease; infectious diseases accompanied by intoxication, exacerbation of chronic hepatitis; sepsis, pre- and postoperative period to improve arterial and venous circulation for the prevention and treatment of thrombosis, thrombophlebitis, endarteritis, and Raynaud's disease.

Ringer's Lactate, solution for infusion will be used as a comparator. As a rehydrating agent, Ringer's Lactate has a detoxification effect, replenishes the deficiency of circulating blood volume, and stabilizes the water and electrolyte composition of blood. Ringer's Lactate normalizes the acid-base balance. Lactate is metabolized in the body to bicarbonate, so the solution has an alkalizing effect. With osmolarity at 273 mOsm/l, Ringer's Lactate is close to isotonic solution and is indicated for hypovolemia, isotonic dehydration, and metabolic alkalosis.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 118
• Est. completion date: March 30, 2021
• Est. primary completion date: September 30, 2020
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 60 Years

Eligibility

Inclusion Criteria:

1. Male and female aged 18 to 60 years inclusive

2. Thermal damage of 2nd stage with a total area of at least 20% and not more than 45% of the body surface.It is acceptable to include patients with deep burns, with a total area from 3% to 15% of the body surface in combination with superficial burns or isolated.

3. Severity of state according to the Frank index from 30 to 90.

4. The duration of the resulting thermal injury no more than 3 days from the planned first administration of the drug

5. Informed consent for participation in the study signed by subject's own hand.

Non-inclusion Criteria:

1. Individual intolerance to components of the study drug and the comparator;

2. Hypersensitivity to sodium lactate;

3. Intravenous infusions of lactate- or sorbitol-containing products within 24 hours before enrollment;

4. Pregnancy or breast-feeding;

5. Severe renal dysfunction (creatinine is more than 300 µmol/l or estimated creatinine clearance is less than 30 ml/min);

6. Metabolic alkalosis;

7. Severe metabolic acidosis;

8. Intracerebral hemorrhage;

9. Any thromboembolism;

10. Decompensated cardiovascular failure;

11. Blood hypertension, grade III (SBP = 180 mm Hg and/or DBP = 90 mm Hg);

12. Conditions associated with immunodeficiency (use of cytotoxic drugs or systemic steroids, AIDS, diabetes mellitus);

13. Extracellular hyperhydration or hypervolemia;

14. Severe renal insufficiency (with oliguria/anuria);

15. Hyperkalemia;

16. Hypercalcemia;

17. Ascites associated with cirrhosis;

18. Conditions associated with increased lactate levels (hyperlactatemia > 2 mmol / l), including lactic acidosis, or impaired lactate uptake (including due severe hepatic insufficiency);

19. Concomitant therapy with cardiac glycosides.

20. The need for artificial ventilation

21. The presence of HIV or other immunodeficiency conditions

22. Diabetes mellitus type I or type II with the need for insulin;

23. The need for hemodialysis or other methods of extracorporeal detoxification

24. Conducting chemotherapy now or within 60 days before enrollment

25. Continuous use of corticosteroids in any form in a dose exceeding the equivalent of 10 mg of prednisolone per day

26. The total burn area is less than 20% or more than 45% of the body surface

27. The presence of deep burns (3 degrees and higher in the ICD-10).

28. Localization of burns in areas that interfere with the infusion of the test drug.

29. The severity of the state according to the Frank index is less than 30 and more than 90 units

Exclusion Criteria:

1. Infusion of the study drug or the comparator is started more than 12 hours after randomization;

2. Withdrawal of the informed consent by the subject;

3. Investigator considers that the infusion therapy with either study drug or comparator may not be continued for safety reasons;

4. Development of conditions that prevent further use of the study drug/comparator before efficacy evaluation visit (Visit 3);

5. Subject needs concomitant therapy prohibited in the study before efficacy evaluation visit (Visit 3);

6. Development of conditions (including serious adverse events) which make it impossible to evaluate the primary endpoint;

7. Confirmation of pregnancy at any time of the study.

Related Conditions & MeSH terms

• Burns
• Intoxication

Intervention

Drug:
• Rheosorbilact®
Administered intravenously (with speed 40-60 drip per minute) at a dose of 600 to 1,000 ml (10 to 15 ml/kg body weight per 24 hours) for 3 days.
• Ringer lactate
Administered intravenously (with speed 40-60 drip per minute) at a dose of 1,000 to 2,500 ml (15 to 40 ml/kg body weight per 24 hours) for 3 days.

Locations

Country	Name	City	State
Kazakhstan	Karaganda State Medical University; Regional Center of Traumatology and Orthopedics named after Professor H.Zh.Makazhanov	Karaganda
Moldova, Republic of	Republic Clinical Hospital of Traumatology and Orthopedy	Chisinau
Ukraine	Kharkiv State Clinical Hospital of Ambulance	Kharkiv
Ukraine	Kyiv City Clinical Hospital ?2; Shupyk National Medical Academy of Postgraduate Education	Kyiv
Ukraine	Vinnytska Pyrohov's State Clinical Hospital	Vinnytsya
Uzbekistan	Republic Scientific Center of Ambulance	Tashkent

Sponsors (1)

Lead Sponsor	Collaborator
Yuria-Pharm

Countries where clinical trial is conducted

Kazakhstan,  Moldova, Republic of,  Ukraine,  Uzbekistan, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	A change in the total SOFA score vs. baseline score upon admission	Sequential Organ Failure Assessment (SOFA) score is composed of scores of six organ systems: R-respiratory, C-cardiovascular, H-hepatic, Co-coagulation, Re-renal, and N-neurological graded from 0 to 4 according to the degree of dysfunction or failure.; The SOFA score ranges from 0 to 24 points. We evaluate initial SOFA score and differences between subsequent scores (?-SOFA scores).	Will be evaluated for the duration of Intensive Care Unit (ICU) stay, at screening (Day 0) and Visit 3 (Day 3) of ICU stay.
Secondary	A change in the total APACHE II score vs. baseline score upon admission	Acute physiology and chronic health evaluation(APACHE) II score is calculated from a patient's age (0-6 points) and 12 physiological parameters (each item 0-4 points): AaDO2 or PaO2 (depending on FiO2), Temperature (rectal), Mean arterial pressure, pH arterial, Heart rate, Respiratory rate, Sodium (serum), Potassium (serum), Creatinine, Hematocrit, White blood cell count, Glasgow Coma Scale and chronic disease health status (0-5 points).; The APACHE II score ranges from 0 to 71 points. We evaluate initial APACHE II score and differences between subsequent scores (?-APACHE II scores).	Will be evaluated for the duration of Intensive Care Unit (ICU) stay, at screening (Day 0) and Visit 3 (Day 3) of ICU stay.
Secondary	A change in the total SAPS II score on day 3 vs. baseline score upon admission	The SAPS II score is made of 17 variables: 12 physiology variables, age, type of admission (scheduled surgical, unscheduled surgical, or medical), and three underlying disease variables (acquired immunodeficiency syndrome, metastatic cancer, and hematologic malignancy).; The SAPS II score ranges from 0 to 160 points. We evaluate initial SAPS II score and differences between subsequent scores (?-SAPS II scores).	Will be evaluated for the duration of Intensive Care Unit (ICU) stay, at screening (Day 0) and Visit 3 (Day 3) of ICU stay.
Secondary	A change in the total Spronk score on day 3 vs. baseline score upon admission	Spronck score is made of 5 main parameters: hemodynamic state (2 points), peripheral circulation (2 points), microvascular variables (1 point), systemic markers of tissue oxygenation (1 point), signs of organ dysfunction (2 points).; Spronk score ranges from 0 to 8 points. A score > 2 indicates the presence of shock. We evaluate initial Spronk score and differences between subsequent scores (?-Spronk scores).	Will be evaluated for the duration of Intensive Care Unit (ICU) stay, at screening (Day 0) and Visit 3 (Day 3) of ICU stay.
Secondary	Concentration of glucose	Concentration of glucose (mmol/L) in blood serum after 8-hour fasting.	Will be evaluated for the duration of Intensive Care Unit (ICU) stay, at screening (Day 0) and Visit 3 (Day 3) of ICU stay.
Secondary	Concentration of lactate.	Concentration of lactate (mmol/L) in blood serum after 8-hour fasting.	Will be evaluated for the duration of Intensive Care Unit (ICU) stay, at screening (Day 0) and Visit 3 (Day 3) of ICU stay.
Secondary	Concentration of pyruvate.	Concentration of pyruvate (mmol/L) in blood serum after 8-hour fasting.	Will be evaluated for the duration of Intensive Care Unit (ICU) stay, at screening (Day 0) and Visit 3 (Day 3) of ICU stay.
Secondary	Concentration of urea.	Concentration of urea (mmol/L) in blood serum after 8-hour fasting.	Will be evaluated for the duration of Intensive Care Unit (ICU) stay, at screening (Day 0) and Visit 3 (Day 3) of ICU stay.
Secondary	Concentration of creatinine.	Concentration of creatinine (µmol/L) in blood serum after 8-hour fasting.	Will be evaluated for the duration of Intensive Care Unit (ICU) stay, at screening (Day 0) and Visit 3 (Day 3) of ICU stay.
Secondary	Concentration of bilirubin.	Concentration of bilirubin (µmol/L) in blood serum after 8-hour fasting.	Will be evaluated for the duration of Intensive Care Unit (ICU) stay, at screening (Day 0) and Visit 3 (Day 3) of ICU stay.
Secondary	Concentration of alanine aminotransferase.	Concentration of alanine aminotransferase (U/L) in blood serum after 8-hour fasting.	Will be evaluated for the duration of Intensive Care Unit (ICU) stay, at screening (Day 0) and Visit 3 (Day 3) of ICU stay.
Secondary	Concentration of aspartate aminotransferase.	Concentration of aspartate aminotransferase (U/L) in blood serum after 8-hour fasting.	Will be evaluated for the duration of Intensive Care Unit (ICU) stay, at screening (Day 0) and Visit 3 (Day 3) of ICU stay.
Secondary	Concentration of lactate dehydrogenase.	Concentration of lactate dehydrogenase (U/L) in blood serum after 8-hour fasting.	Will be evaluated for the duration of Intensive Care Unit (ICU) stay, at screening (Day 0) and Visit 3 (Day 3) of ICU stay.
Secondary	Concentration of alkaline phosphatase.	Concentration of alkaline phosphatase (U/L) in blood serum after 8-hour fasting.	Will be evaluated for the duration of Intensive Care Unit (ICU) stay, at screening (Day 0) and Visit 3 (Day 3) of ICU stay.
Secondary	Concentration of creatine kinase.	Concentration of creatine kinase (U/L) in blood serum after 8-hour fasting.	Will be evaluated for the duration of Intensive Care Unit (ICU) stay, at screening (Day 0) and Visit 3 (Day 3) of ICU stay.
Secondary	Concentration of ?-Glutamyltransferase.	Concentration of ?-Glutamyltransferase (U/L) in blood serum after 8-hour fasting.	Will be evaluated for the duration of Intensive Care Unit (ICU) stay, at screening (Day 0) and Visit 3 (Day 3) of ICU stay.
Secondary	Concentration of low-molecular-weight adiponectin (LMW).	Concentration of low-molecular-weight adiponectin (U/L) in blood serum after 8-hour fasting.	Will be evaluated for the duration of Intensive Care Unit (ICU) stay, at screening (Day 0) and Visit 3 (Day 3) of ICU stay.
Secondary	Concentration of middle-molecular-weight adiponectin (MMW).	Concentration of middle-molecular-weight adiponectin (U/L) in blood serum after 8-hour fasting.	Will be evaluated for the duration of Intensive Care Unit (ICU) stay, at screening (Day 0) and Visit 3 (Day 3) of ICU stay.
Secondary	Concentration of albumin.	Concentration of albumin in blood serum after 8-hour fasting.	Will be evaluated for the duration of Intensive Care Unit (ICU) stay, at screening (Day 0) and Visit 3 (Day 3) of ICU stay.
Secondary	Procalcitonin level.	Concentration of procalcitonin level (µg/L) in blood serum after 8-hour fasting.	Will be evaluated for the duration of Intensive Care Unit (ICU) stay, at screening (Day 0) and Visit 3 (Day 3) of ICU stay.
Secondary	White blood cells (WBC) count level.	White blood cells (billion/L) count level in blood serum after 8-hour fasting.	Will be evaluated for the duration of Intensive Care Unit (ICU) stay, at screening (Day 0) and Visit 3 (Day 3) of ICU stay.
Secondary	Lymphocyte count level.	Lymphocyte count (%) level in blood serum after 8-hour fasting.	Will be evaluated for the duration of Intensive Care Unit (ICU) stay, at screening (Day 0) and Visit 3 (Day 3) of ICU stay.
Secondary	Platelet count level.	Platelet count level (billion/L) in blood serum after 8-hour fasting.	Will be evaluated for the duration of Intensive Care Unit (ICU) stay, at screening (Day 0) and Visit 3 (Day 3) of ICU stay.
Secondary	Calculation of Nuclear index of intoxication (NII)	Calculated by dividing the number of myelocytes, young and stab neutrophils by number of segmented neutrophils.	Will be evaluated for the duration of Intensive Care Unit (ICU) stay, at screening (Day 0) and Visit 3 (Day 3) of ICU stay.
Secondary	Calculation of Leukocyte index of intoxication (LII).	Calculated by the formula of Kalf-Kalifa: correlation between the level of neutrophils and the content of other cells in the blood leukocytic composition.	Will be evaluated for the duration of Intensive Care Unit (ICU) stay, at screening (Day 0) and Visit 3 (Day 3) of ICU stay.
Secondary	Concentration of C-reactive protein (CRP).	Concentration of C-reactive protein (CRP) in blood serum after 8-hour fasting.	Will be evaluated for the duration of Intensive Care Unit (ICU) stay, at screening (Day 0) and Visit 3 (Day 3) of ICU stay.
Secondary	Level of circulating immune complexes (CIC).	Level of Circulating immune complexes (CIC) in blood serum after 8-hour fasting.	Will be evaluated for the duration of Intensive Care Unit (ICU) stay, at screening (Day 0) and Visit 3 (Day 3) of ICU stay.
Secondary	Concentration of Interleukin-1 and 2.	Concentration of Interleukin-1 (pg/ml) and Interleukin-2 (pg/ml) in blood serum after 8-hour fasting.	Will be evaluated for the duration of Intensive Care Unit (ICU) stay, at screening (Day 0) and Visit 3 (Day 3) of ICU stay.
Secondary	Calculation of neutrophil-to-lymphocyte ratio (NLR).	Calculated by dividing the number of neutrophils (%) by number of lymphocytes (%).	Will be evaluated for the duration of Intensive Care Unit (ICU) stay, at screening (Day 0) and Visit 3 (Day 3) of ICU stay.
Secondary	Concentration of immunoglobulins.	Concentration of Ig A, Ig M and Ig G in blood serum after 8-hour fasting.	Will be evaluated for the duration of Intensive Care Unit (ICU) stay, at screening (Day 0) and Visit 3 (Day 3) of ICU stay.
Secondary	Concentration of complements.	Concentration of complements (C3, C4) in blood sample after 8-hour fasting.	Will be evaluated for the duration of Intensive Care Unit (ICU) stay, at screening (Day 0) and Visit 3 (Day 3) of ICU stay.
Secondary	Assessment of central hemodynamics.	Measurement of central venous pressure (mmh2o) in the central vein.	Will be evaluated for the duration of Intensive Care Unit (ICU) stay, at screening (Day 0) and Visit 3 (Day 3) of ICU stay.
Secondary	A change in the total Glasgow Coma Scale (GCS) score vs. baseline score upon admission	The GCS is composed of 3 components: ocular response (assessment 1-4 points), motor response (assessment 1-6 points) verbal response (evaluation of 1-5 points). Scores for each component are added together to get the total that will range between a minimum of 3 points (which corresponds to a patient who does not open his eyes and no motor response to stimulation or verbal response) and a maximum value of 15 points (corresponding to a patient with open eyes, obeying orders and maintaining a consistent language).	Will be evaluated for the duration of Intensive Care Unit (ICU) stay, at screening (Day 0) and Visit 3 (Day 3) of ICU stay.
Secondary	Measurement of 12-lead electrocardiogram (ECG).	Measurement of 12-lead ECG with further evaluation and interpretation whether the ECG waves, intervals, durations and rhythm are normal.	Will be evaluated for the duration of Intensive Care Unit (ICU) stay, at screening (Day 0) and Visit 3 (Day 3) of ICU stay.
Secondary	Number of participants with Presence of clinical signs.	Number of participants with presence of clinical signs such as adynamia, weakness, memory impairment, sleep disorder, irritability, evaluated according to patient's subjective complaints.	Will be evaluated for the duration of Intensive Care Unit (ICU) stay, at screening (Day 0) and Visit 3 (Day 3) of ICU stay.
Secondary	Incidence of Treatment-Emergent Adverse events	All types of adverse events	Patients will be followed during 14 days.
Secondary	Incidence of multiple organ failure	Incidence of multiple organ failure	Patients will be followed during 14 days.
Secondary	Overall survival (%) at follow-up visit.	Overall survival (%) at follow-up visit.	Follow-up visit (Day 14±1)