Clinical trial NCT03764085: Efficacy and Safety of Rheosorbilact® Solution for Infusion, in a Complex Therapy of Sepsis.
Official title: Open-label, Randomized, Controlled, With Blind Assessor, Study to Assess Efficacy and Safety of Rheosorbilact®, Solution for Infusion, in Comparison With Ringer's Lactate, Solution for Infusion, in a Complex Therapy of Sepsis.
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Sepsis
Intoxication; Septic
Lead sponsor: Yuria-Pharm
Sponsor class: INDUSTRY
First posted: 2018-12-04
Enrollment: 180
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 sepsis. 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. Sepsis diagnosed according to ACCP / SCCM criteria (no later than 24 hours from the time of diagnosis of sepsis to screening visit) (Annex 1: Sequence Diagnostic Criteria for SCCM / ESICM / ACCP / ATS / SIS)
3. Informed consent for participation in the study signed by subject's own hand.
4. The baseline value of the SOFA scale ≥ 2 points.

Non-inclusion Criteria:

1. The presence of any of the criteria for severe sepsis by ACCP / SCCM (presence of signs of organ failure - Annex 1: criteria for diagnosis of sepsis SCCM / ESICM / ACCP / ATS / SIS)
2. Individual intolerance of the components of the study drug and the comparator;
3. Hypersensitivity to sodium lactate;
4. Intravenous infusions of lactate- or sorbitol-containing products within 24 hours before enrollment;
5. Pregnancy or breast-feeding;
6. Severe renal dysfunction (creatinine is more than 300 μmol/l or estimated creatinine clearance is less than 30 ml/min);
7. Metabolic alkalosis;
8. Severe metabolic acidosis;
9. Intracerebral hemorrhage;
10. Any thromboembolism;
11. Decompensated cardiovascular failure;
12. Arterial hypertension III st;
13. Conditions associated with immunodeficiency (the use of cytostatics or system steroids, AIDS);
14. Extracellular hyperhydration or hypervolemia;
15. Severe renal insuffiency (with oliguria / anuria);
16. Hyperkalaemia;
17. Hypercalcemia;
18. Ascites associated with cirrhosis;
19. Conditions associated with increased lactate levels (hyperlactatemia \> 2 mmol / l), including lactic acidosis, or impaired lactate uptake (including due severe hepatic insufficiency);
20. Concomitant therapy with cardiac glycosides;

Exclusion Criteria:

1. Infusion of the study drug or the comparator is started more than 12 hours after randomization;
2. Lack of data for sepsis (diagnosis not confirmed);
3. Withdrawal of the informed consent by the subject;
4. Investigator considers that the infusion therapy with either study drug or comparator may not be continued for safety reasons;
5. Development of conditions that prevent further use of the study drug/comparator before efficacy evaluation visit (Visit 3);
6. Subject needs concomitant therapy prohibited in the study before efficacy evaluation visit (Visit 3);
7. Development of conditions (including serious adverse events) which make it impossible to evaluate the primary endpoint;
8. 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 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 MODS 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: 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 sodium
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 potassium
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: Assessment of 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: 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.
Other outcomes:
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)
Locations:
city: Batumi
country: Georgia
facility: "Unimedi Adjara" LLC
city: Kutaisi
country: Georgia
facility: Kutaisi Referral Hospital
city: Astana
country: Kazakhstan
facility: Hospital of the Medical Center of the Administration of the President of the Republic of Kazakhstan
city: Chisinau
country: Moldova, Republic of
facility: Institute of Ambulance
city: Chisinau
country: Moldova, Republic of
facility: Municipal Clinical Hospital "Sfinta Treime"
city: Chisinau
country: Moldova, Republic of
facility: Republican Clinical Hospital
city: Dnipro
country: Ukraine
facility: Dnipro's Medical Academy of Ministry of Health of Ukraine
city: Kharkiv
country: Ukraine
facility: Zaicev's Institute of general and urgent surgery NMA Ukraine
city: Khmelnytskyi
country: Ukraine
facility: Khmelnytskyi Regional Clinical Hospital
city: Poltava
country: Ukraine
facility: HSEE of Ukraine "Ukrainian Medical Stomatological Academy"; Poltava Central District Hospital
city: Vinnitsa
country: Ukraine
facility: Central District Clinical Hospital
city: Zaporizhzhya
country: Ukraine
facility: Zaporizka Medical Academy of postgraduate education, Zaporizkyi Clinical Hospital N9
city: Tashkent
country: Uzbekistan
facility: Republic Centre of Ambulance
Study officials:
References: