Clinical trial NCT04152096: Efficacy and Safety of Rheosorbilact® Solution for Infusion, in a Complex Therapy of Burns
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Burns
Intoxication
Lead sponsor: Yuria-Pharm
Sponsor class: INDUSTRY
First posted: 2019-11-05
Enrollment: 118
Sex: ALL
Minimum age (years): 18
Maximum age (years): 60
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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.

Detailed 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.

Eligibility criteria: 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.

Primary outcomes:
measure: A change in the total SOFA score vs. baseline score upon admission
timeFrame: 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 outcomes:
measure: A change in the total APACHE II score vs. baseline score upon admission
timeFrame: Will be evaluated for the duration of Intensive Care Unit (ICU) stay, at screening (Day 0) and Visit 3 (Day 3) of ICU stay.
measure: A change in the total SAPS II score on day 3 vs. baseline score upon admission
timeFrame: Will be evaluated for the duration of Intensive Care Unit (ICU) stay, at screening (Day 0) and Visit 3 (Day 3) of ICU stay.
measure: A change in the total Spronk score on day 3 vs. baseline score upon admission
timeFrame: Will be evaluated for the duration of Intensive Care Unit (ICU) stay, at screening (Day 0) and Visit 3 (Day 3) of ICU stay.
measure: Concentration of glucose
timeFrame: Will be evaluated for the duration of Intensive Care Unit (ICU) stay, at screening (Day 0) and Visit 3 (Day 3) of ICU stay.
measure: Concentration of lactate.
timeFrame: Will be evaluated for the duration of Intensive Care Unit (ICU) stay, at screening (Day 0) and Visit 3 (Day 3) of ICU stay.
measure: Concentration of pyruvate.
timeFrame: Will be evaluated for the duration of Intensive Care Unit (ICU) stay, at screening (Day 0) and Visit 3 (Day 3) of ICU stay.
measure: Concentration of urea.
timeFrame: Will be evaluated for the duration of Intensive Care Unit (ICU) stay, at screening (Day 0) and Visit 3 (Day 3) of ICU stay.
measure: Concentration of creatinine.
timeFrame: Will be evaluated for the duration of Intensive Care Unit (ICU) stay, at screening (Day 0) and Visit 3 (Day 3) of ICU stay.
measure: Concentration of bilirubin.
timeFrame: Will be evaluated for the duration of Intensive Care Unit (ICU) stay, at screening (Day 0) and Visit 3 (Day 3) of ICU stay.
measure: Concentration of alanine aminotransferase.
timeFrame: Will be evaluated for the duration of Intensive Care Unit (ICU) stay, at screening (Day 0) and Visit 3 (Day 3) of ICU stay.
measure: Concentration of aspartate aminotransferase.
timeFrame: Will be evaluated for the duration of Intensive Care Unit (ICU) stay, at screening (Day 0) and Visit 3 (Day 3) of ICU stay.
measure: Concentration of lactate dehydrogenase.
timeFrame: Will be evaluated for the duration of Intensive Care Unit (ICU) stay, at screening (Day 0) and Visit 3 (Day 3) of ICU stay.
measure: Concentration of alkaline phosphatase.
timeFrame: Will be evaluated for the duration of Intensive Care Unit (ICU) stay, at screening (Day 0) and Visit 3 (Day 3) of ICU stay.
measure: Concentration of creatine kinase.
timeFrame: Will be evaluated for the duration of Intensive Care Unit (ICU) stay, at screening (Day 0) and Visit 3 (Day 3) of ICU stay.
measure: Concentration of γ-Glutamyltransferase.
timeFrame: Will be evaluated for the duration of Intensive Care Unit (ICU) stay, at screening (Day 0) and Visit 3 (Day 3) of ICU stay.
measure: Concentration of low-molecular-weight adiponectin (LMW).
timeFrame: Will be evaluated for the duration of Intensive Care Unit (ICU) stay, at screening (Day 0) and Visit 3 (Day 3) of ICU stay.
measure: Concentration of middle-molecular-weight adiponectin (MMW).
timeFrame: Will be evaluated for the duration of Intensive Care Unit (ICU) stay, at screening (Day 0) and Visit 3 (Day 3) of ICU stay.
measure: Concentration of albumin.
timeFrame: Will be evaluated for the duration of Intensive Care Unit (ICU) stay, at screening (Day 0) and Visit 3 (Day 3) of ICU stay.
measure: Procalcitonin level.
timeFrame: Will be evaluated for the duration of Intensive Care Unit (ICU) stay, at screening (Day 0) and Visit 3 (Day 3) of ICU stay.
measure: White blood cells (WBC) count level.
timeFrame: Will be evaluated for the duration of Intensive Care Unit (ICU) stay, at screening (Day 0) and Visit 3 (Day 3) of ICU stay.
measure: Lymphocyte count level.
timeFrame: Will be evaluated for the duration of Intensive Care Unit (ICU) stay, at screening (Day 0) and Visit 3 (Day 3) of ICU stay.
measure: Platelet count level.
timeFrame: Will be evaluated for the duration of Intensive Care Unit (ICU) stay, at screening (Day 0) and Visit 3 (Day 3) of ICU stay.
measure: Calculation of Nuclear index of intoxication (NII)
timeFrame: Will be evaluated for the duration of Intensive Care Unit (ICU) stay, at screening (Day 0) and Visit 3 (Day 3) of ICU stay.
measure: Calculation of Leukocyte index of intoxication (LII).
timeFrame: Will be evaluated for the duration of Intensive Care Unit (ICU) stay, at screening (Day 0) and Visit 3 (Day 3) of ICU stay.
measure: Concentration of C-reactive protein (CRP).
timeFrame: Will be evaluated for the duration of Intensive Care Unit (ICU) stay, at screening (Day 0) and Visit 3 (Day 3) of ICU stay.
measure: Level of circulating immune complexes (CIC).
timeFrame: Will be evaluated for the duration of Intensive Care Unit (ICU) stay, at screening (Day 0) and Visit 3 (Day 3) of ICU stay.
measure: Concentration of Interleukin-1 and 2.
timeFrame: Will be evaluated for the duration of Intensive Care Unit (ICU) stay, at screening (Day 0) and Visit 3 (Day 3) of ICU stay.
measure: Calculation of neutrophil-to-lymphocyte ratio (NLR).
timeFrame: Will be evaluated for the duration of Intensive Care Unit (ICU) stay, at screening (Day 0) and Visit 3 (Day 3) of ICU stay.
measure: Concentration of immunoglobulins.
timeFrame: Will be evaluated for the duration of Intensive Care Unit (ICU) stay, at screening (Day 0) and Visit 3 (Day 3) of ICU stay.
measure: Concentration of complements.
timeFrame: Will be evaluated for the duration of Intensive Care Unit (ICU) stay, at screening (Day 0) and Visit 3 (Day 3) of ICU stay.
measure: Assessment of central hemodynamics.
timeFrame: Will be evaluated for the duration of Intensive Care Unit (ICU) stay, at screening (Day 0) and Visit 3 (Day 3) of ICU stay.
measure: A change in the total Glasgow Coma Scale (GCS) score vs. baseline score upon admission
timeFrame: Will be evaluated for the duration of Intensive Care Unit (ICU) stay, at screening (Day 0) and Visit 3 (Day 3) of ICU stay.
measure: Measurement of 12-lead electrocardiogram (ECG).
timeFrame: Will be evaluated for the duration of Intensive Care Unit (ICU) stay, at screening (Day 0) and Visit 3 (Day 3) of ICU stay.
measure: Number of participants with Presence of clinical signs.
timeFrame: Will be evaluated for the duration of Intensive Care Unit (ICU) stay, at screening (Day 0) and Visit 3 (Day 3) of ICU stay.
measure: Incidence of Treatment-Emergent Adverse events
timeFrame: Patients will be followed during 14 days.
measure: Incidence of multiple organ failure
timeFrame: Patients will be followed during 14 days.
measure: Overall survival (%) at follow-up visit.
timeFrame: Follow-up visit (Day 14±1)
Other outcomes:
Locations:
city: Karaganda
country: Kazakhstan
facility: Karaganda State Medical University; Regional Center of Traumatology and Orthopedics named after Professor H.Zh.Makazhanov
city: Chisinau
country: Moldova, Republic of
facility: Republic Clinical Hospital of Traumatology and Orthopedy
city: Kyiv
country: Ukraine
facility: Kyiv City Clinical Hospital №2; Shupyk National Medical Academy of Postgraduate Education
city: Vinnytsya
country: Ukraine
facility: Vinnytska Pyrohov's State Clinical Hospital
city: Tashkent
country: Uzbekistan
facility: Republic Scientific Center of Ambulance
Study officials:
References: