Ignite Creation Date:
2024-05-06 @ 7:54 PM
Last Modification Date:
2024-10-26 @ 3:16 PM
Study NCT ID:
NCT06170372
Status:
RECRUITING
Last Update Posted:
2024-02-02
First Post:
2023-12-06
Brief Title:
High-dose Inhalations of Nitric Oxide in the Treatment of Pneumonia
Sponsor:
Tomsk National Research Medical Center of the Russian Academy of Sciences
Organization:
Tomsk National Research Medical Center of the Russian Academy of Sciences
Study Overview
Official Title:
The Effectiveness of Adding Multiple Intermittent High-dose Inhalations of Nitric Oxide to Standard Antibacterial Therapy in the Treatment of Pneumonia
Status:
RECRUITING
Status Verified Date:
2024-02
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
This is a multicenter prospective randomized controlled trial At least 2 but no more than 5 centers are expected to participate in the study
The primary objective is to test the hypothesis that the addition of high-dose inhaled nitric oxide therapy to standard treatment has a positive effect on the clinical course of pneumonia and the structure and function of cardiopulmonary system
Number of participants 200 including the subproject NO-PNEUMONIA-CAP - 100 CAP participants the subproject NO-PNEUMONIA-NP - 100 NP participants
Number of groups 4 Inhalation of iNO at a dose of 200 ppm for 30 minutes under the control of methemoglobin level no more than 5 three times a day if the patient is allocated to the main group The general course of iNO therapy will last until the pneumonia resolves but no more than 7 days Recording of vital signs and safety assessment will be carried out immediately before the initiation of NO therapy and every 15 minutes after its start pulse blood pressure respiratory rate SpO2 temperature MetHb level
The primary objective is to test the hypothesis that the addition of high-dose inhaled nitric oxide therapy to standard treatment has a positive effect on the clinical course of pneumonia and the structure and function of cardiopulmonary system
Number of participants 200 including the subproject NO-PNEUMONIA-CAP - 100 CAP participants the subproject NO-PNEUMONIA-NP - 100 NP participants
Number of groups 4 Inhalation of iNO at a dose of 200 ppm for 30 minutes under the control of methemoglobin level no more than 5 three times a day if the patient is allocated to the main group The general course of iNO therapy will last until the pneumonia resolves but no more than 7 days Recording of vital signs and safety assessment will be carried out immediately before the initiation of NO therapy and every 15 minutes after its start pulse blood pressure respiratory rate SpO2 temperature MetHb level
Detailed Description:
Principal investigator TP Kalashnikova MD PhD Sub-investigators NOKamenshchikov MD PhD IV Kravchenko MD YuA Arsenyeva MD YuK Podoksenov MD PhD DMedSci MS Kozulin MD MB Gorchakova MD BN Kozlov MD PhD DMedSci AA Boshchenko MD PhD DMedSci
RESEARCH RELEVANCE Pneumonia remains one of the most common infectious respiratory diseases worldwide Community-acquired pneumonia CAP is defined as pneumonia that is acquired outside the hospital or diagnosed in the first 48 hours from hospitalization Nosocomial pneumonia NP is diagnosed in individuals with symptoms of the disease that develop 48 hours or more after the patients hospitalization The most common causative agents of CAP are S pneumoniae M pneumoniae C pneumoniae H influenza as well as viruses and microbial associations In recent years there has been an increase in the resistance of CAP pathogens to antibiotics of the group of aminopenicillins cephalosporins and macrolides
In the etiological structure of NP the leading role belongs to gram-negative microorganisms The main pathogens are representatives of Enterobacteriaceae including Klebsiella pneumoniae and Ecoli Acinetobacter baumannii Pseudomonas aeruginosa characterized by a high level of resistance to antimicrobial drugs
Considering the high prevalence of pneumonia the continuous increase in the resistance of microorganisms to antimicrobial agents the high mortality rate from adverse reactions caused by multidrug-resistant bacteria the lack of development of new drugs with proven antibacterial effectiveness and the high economic costs of treatment it is urgent to search for alternative ways to increase efficiency in the treatment of pneumonia From this point of view the addition of inhaled high doses of nitric oxide iNO to standard antibacterial therapy seems promising
The positive results of using NO have been proven in the treatment of patients with pulmonary hypertension chronic obstructive pulmonary disease acute respiratory distress syndrome ARDS and in the treatment of wound processes There is a cardioprotective and nephroprotective effect of this molecule that has been described In recent years data have appeared on the successful use of iNO in the treatment of viral pneumonia in particular in pneumonia caused by the Severe acute respiratory syndrome-related coronavirus 2 SARS-CoV2 High concentrations of nitric oxide cause cytotoxic antibacterial antiviral and antifungal effects
The use of iNO for pneumonia is pathogenetically justified It has a selective vasodilating effect on pulmonary blood vessels with no systemic effect on hemodynamics By reducing vascular resistance in the ventilated areas of lungs it improves ventilation-perfusion ratio and can increase systemic oxygenation reduce pulmonary hypertension and right ventricular dysfunction and promotes the inclusion of previously unventilated alveoli in gas exchange
The use of NO appears even more justified in the treatment of pneumonia in patients undergoing cardiac surgery under cardiopulmonary bypass CPB since their lungs are subject to ischemia and reperfusion injury during CPB
In recent years more and more evidence has emerged that the mechanisms of antimicrobial action of NO differ from those of modern traditional antibiotics which is most relevant in the treatment of infections caused by multidrug-resistant bacteria and polymicrobial infections
The antibacterial effect of NO at a dose of 160 ppm parts per million and higher has been described for a number of microorganisms The safety of using iNO for humans in doses of 160-200 ppm for 15-30 minutes 2 to 5 times a day has been demonstrated in a number of clinical studies with Mycobacterium abscessus other complex clinical situations in patients with cystic fibrosis in pregnant women and newborns In contrast to bacterial membranes sensitive to NO the stability of membranes of epithelial cells and fibroblasts and the absence of cytolysis when exposed to nitric oxide 200 ppm 3 times a day was proven in experimental studies and on cells of living human tissues
PRIMARY OBJECTIVE To test the hypothesis that the addition of high-dose inhaled nitric oxide therapy to standard treatment has a positive effect on the clinical course of pneumonia and the structure and function of cardiopulmonary system
SECONDARY OBJECTIVES
To assess the timing of resolution of pneumonia in the main with iNO and control without iNO groups
To assess differences in the dynamics of acute phase reactants in the main and control groups
To assess differences in the X-ray of the lungs and its dynamics in the main and control groups
To assess differences in variables of the functional state of the lungs and their dynamics according to spirometry and the 6-minute walk test under the influence of therapy in the main and control groups
To study differences in the dynamics of the main variables of the structural and functional state of the heart during echocardiography in the main and control groups
The effectiveness of the study will be assessed by such a concept as end point
The primary composite endpoint will be resolution of pneumonia The term resolution of pneumonia will include three criteria achieving an oxygenation index SpO2fraction of inspired oxygen FiO2 315 Respiratory Rate RR20 discontinuation of antibacterial therapy
Secondary hospital endpoints
1 Difference in the duration of systemic inflammatory response syndrome fever leukocytosis a shift in the white blood cells WBC towards more immature cells increased levels of C-reactive protein CRP procalcitonin PCT in the study groups
2 Difference in the duration of respiratory support in the study groups
3 Difference in the frequency of changing antibacterial treatment regimens due to ineffectiveness in the compared study groups
4 Difference in the frequency of transfer of patients to non-invasive ventilation NIV mechanical ventilation in the study groups
5 Difference in the incidence of sepsis and septic shock in both groups
6 Difference in the frequency of decrease in oxygen saturation after 72 hours from the start of therapy below 95 with an initially normal level or by 3 or more with an initially reduced level in the main and control groups
7 Difference in the frequency of negative computer tomography CT dynamics after 72 hours of therapy in the study groups
8 Difference in the frequency of increase in right atrial and ventricle volume index andor peak tricuspid regurgitation velocity andor decrease in contractile function of the right ventricle after 72 hours of therapy and with the resolution of pneumonia in groups
9 Difference in the distance traveled according to the 6-minute walk test 6MWT with the resolution of pneumonia in the main and control groups
10 Difference in the frequency and severity of the development of ventilatory disorders during spirometry at the time of resolution of pneumonia in the main and control groups
11 Difference in scores according to EQ-5D-5L quality of life questionnaire in the main and control groups
12 Difference in the percentage of mortality caused by pneumonia or its complications sepsis multiple organ failure acute respiratory failure in the compared groups
The study will include patients who underwent cardiac surgery under CPB with NP diagnosed in the postoperative period as well as patients hospitalized for CAP Patients will be randomized into 4 groups
Subproject NO-PNEUMONIA-NP Group 1 main group n50 Standard antibacterial therapy NO 200 ppm 3 times a day for 30 minutes Group 2 control group n50 Standard antibacterial therapy Subproject NO-PNEUMONIA-CAP Group 3 main group n50 Standard antibacterial therapy NO 200 ppm 3 times a day for 30 minutes Group 4 control group n50 Standard antibacterial therapy A special device which synthesizes nitric oxide from atmospheric air directly during therapy will be used The technology is based on the process of oxidation of atmospheric nitrogen in a nonequilibrium gas discharge plasma and is characterized by high operating accuracy and stable maintenance of NO concentration in the breathing mixture
ASSESSMENT OF CLINICAL EFFECTIVENESS Clinical effectiveness will be assessed daily with registration of data at control points day of development of pneumonia 72 hours from the onset of the disease resolution of pneumonia according to the dynamics of the temperature curve oxygen saturation SpO2 respiratory rate oxygenation index SpO2FiO2 assessment of quality of life according to European Quality-of-Life-5 Dimension EQ -5D-5L questionnaire
LABORATORY ASSESSMENT Laboratory effectiveness will be assessed by the levels of peripheral blood leukocytes the significance of blood shift in the leukocyte formula the dynamics of CRP PCT screening 72 hours from the onset of the disease resolution of pneumonia
ASSESSMENT OF INSTRUMENTAL EFFICIENCY
1 Distance traveled during the 6-minute walk test on the day the pneumonia resolved
2 Spirometry will be performed on the day of screening and on the day of resolution of pneumonia and include assessment of Vital capacity Forced vital capacity Forced expiratory volume in one second Peak expiratory flow Forced expiratory flow at 25 of Forced vital capacity FVC Forced expiratory flow at 50 of FVC Forced expiratory flow at 75 of FVC
3 Chest CT scan on the day of screening after 72 hours and on the day of resolution of pneumonia with determination of localization and size of consolidation localization and size of the Ground-glass opacity air bronchograms yesno hemodynamic abnormalities yesno fluid volume in the pleural cavities
4 Cardiac ultrasound will be performed on the day of screening 72 hours later and on the day of resolution of pneumonia and will include assessment of end-diastolic end-systolic volume indexes and left ventricular ejection fraction right ventricular antero-posterior diameter right ventricular fractional area change tricuspid regurgitation velocity Tricuspid annular plane systolic excursion TAPSE tricuspid annular systolic velocity S right ventricular free wall longitudinal strain if possible diameter of the inferior vena cava and its collapse during inspiration fluid in the pericardial cavity yesno volume insignificantmoderateseveretamponade and pleural cavities
RESEARCH RELEVANCE Pneumonia remains one of the most common infectious respiratory diseases worldwide Community-acquired pneumonia CAP is defined as pneumonia that is acquired outside the hospital or diagnosed in the first 48 hours from hospitalization Nosocomial pneumonia NP is diagnosed in individuals with symptoms of the disease that develop 48 hours or more after the patients hospitalization The most common causative agents of CAP are S pneumoniae M pneumoniae C pneumoniae H influenza as well as viruses and microbial associations In recent years there has been an increase in the resistance of CAP pathogens to antibiotics of the group of aminopenicillins cephalosporins and macrolides
In the etiological structure of NP the leading role belongs to gram-negative microorganisms The main pathogens are representatives of Enterobacteriaceae including Klebsiella pneumoniae and Ecoli Acinetobacter baumannii Pseudomonas aeruginosa characterized by a high level of resistance to antimicrobial drugs
Considering the high prevalence of pneumonia the continuous increase in the resistance of microorganisms to antimicrobial agents the high mortality rate from adverse reactions caused by multidrug-resistant bacteria the lack of development of new drugs with proven antibacterial effectiveness and the high economic costs of treatment it is urgent to search for alternative ways to increase efficiency in the treatment of pneumonia From this point of view the addition of inhaled high doses of nitric oxide iNO to standard antibacterial therapy seems promising
The positive results of using NO have been proven in the treatment of patients with pulmonary hypertension chronic obstructive pulmonary disease acute respiratory distress syndrome ARDS and in the treatment of wound processes There is a cardioprotective and nephroprotective effect of this molecule that has been described In recent years data have appeared on the successful use of iNO in the treatment of viral pneumonia in particular in pneumonia caused by the Severe acute respiratory syndrome-related coronavirus 2 SARS-CoV2 High concentrations of nitric oxide cause cytotoxic antibacterial antiviral and antifungal effects
The use of iNO for pneumonia is pathogenetically justified It has a selective vasodilating effect on pulmonary blood vessels with no systemic effect on hemodynamics By reducing vascular resistance in the ventilated areas of lungs it improves ventilation-perfusion ratio and can increase systemic oxygenation reduce pulmonary hypertension and right ventricular dysfunction and promotes the inclusion of previously unventilated alveoli in gas exchange
The use of NO appears even more justified in the treatment of pneumonia in patients undergoing cardiac surgery under cardiopulmonary bypass CPB since their lungs are subject to ischemia and reperfusion injury during CPB
In recent years more and more evidence has emerged that the mechanisms of antimicrobial action of NO differ from those of modern traditional antibiotics which is most relevant in the treatment of infections caused by multidrug-resistant bacteria and polymicrobial infections
The antibacterial effect of NO at a dose of 160 ppm parts per million and higher has been described for a number of microorganisms The safety of using iNO for humans in doses of 160-200 ppm for 15-30 minutes 2 to 5 times a day has been demonstrated in a number of clinical studies with Mycobacterium abscessus other complex clinical situations in patients with cystic fibrosis in pregnant women and newborns In contrast to bacterial membranes sensitive to NO the stability of membranes of epithelial cells and fibroblasts and the absence of cytolysis when exposed to nitric oxide 200 ppm 3 times a day was proven in experimental studies and on cells of living human tissues
PRIMARY OBJECTIVE To test the hypothesis that the addition of high-dose inhaled nitric oxide therapy to standard treatment has a positive effect on the clinical course of pneumonia and the structure and function of cardiopulmonary system
SECONDARY OBJECTIVES
To assess the timing of resolution of pneumonia in the main with iNO and control without iNO groups
To assess differences in the dynamics of acute phase reactants in the main and control groups
To assess differences in the X-ray of the lungs and its dynamics in the main and control groups
To assess differences in variables of the functional state of the lungs and their dynamics according to spirometry and the 6-minute walk test under the influence of therapy in the main and control groups
To study differences in the dynamics of the main variables of the structural and functional state of the heart during echocardiography in the main and control groups
The effectiveness of the study will be assessed by such a concept as end point
The primary composite endpoint will be resolution of pneumonia The term resolution of pneumonia will include three criteria achieving an oxygenation index SpO2fraction of inspired oxygen FiO2 315 Respiratory Rate RR20 discontinuation of antibacterial therapy
Secondary hospital endpoints
1 Difference in the duration of systemic inflammatory response syndrome fever leukocytosis a shift in the white blood cells WBC towards more immature cells increased levels of C-reactive protein CRP procalcitonin PCT in the study groups
2 Difference in the duration of respiratory support in the study groups
3 Difference in the frequency of changing antibacterial treatment regimens due to ineffectiveness in the compared study groups
4 Difference in the frequency of transfer of patients to non-invasive ventilation NIV mechanical ventilation in the study groups
5 Difference in the incidence of sepsis and septic shock in both groups
6 Difference in the frequency of decrease in oxygen saturation after 72 hours from the start of therapy below 95 with an initially normal level or by 3 or more with an initially reduced level in the main and control groups
7 Difference in the frequency of negative computer tomography CT dynamics after 72 hours of therapy in the study groups
8 Difference in the frequency of increase in right atrial and ventricle volume index andor peak tricuspid regurgitation velocity andor decrease in contractile function of the right ventricle after 72 hours of therapy and with the resolution of pneumonia in groups
9 Difference in the distance traveled according to the 6-minute walk test 6MWT with the resolution of pneumonia in the main and control groups
10 Difference in the frequency and severity of the development of ventilatory disorders during spirometry at the time of resolution of pneumonia in the main and control groups
11 Difference in scores according to EQ-5D-5L quality of life questionnaire in the main and control groups
12 Difference in the percentage of mortality caused by pneumonia or its complications sepsis multiple organ failure acute respiratory failure in the compared groups
The study will include patients who underwent cardiac surgery under CPB with NP diagnosed in the postoperative period as well as patients hospitalized for CAP Patients will be randomized into 4 groups
Subproject NO-PNEUMONIA-NP Group 1 main group n50 Standard antibacterial therapy NO 200 ppm 3 times a day for 30 minutes Group 2 control group n50 Standard antibacterial therapy Subproject NO-PNEUMONIA-CAP Group 3 main group n50 Standard antibacterial therapy NO 200 ppm 3 times a day for 30 minutes Group 4 control group n50 Standard antibacterial therapy A special device which synthesizes nitric oxide from atmospheric air directly during therapy will be used The technology is based on the process of oxidation of atmospheric nitrogen in a nonequilibrium gas discharge plasma and is characterized by high operating accuracy and stable maintenance of NO concentration in the breathing mixture
ASSESSMENT OF CLINICAL EFFECTIVENESS Clinical effectiveness will be assessed daily with registration of data at control points day of development of pneumonia 72 hours from the onset of the disease resolution of pneumonia according to the dynamics of the temperature curve oxygen saturation SpO2 respiratory rate oxygenation index SpO2FiO2 assessment of quality of life according to European Quality-of-Life-5 Dimension EQ -5D-5L questionnaire
LABORATORY ASSESSMENT Laboratory effectiveness will be assessed by the levels of peripheral blood leukocytes the significance of blood shift in the leukocyte formula the dynamics of CRP PCT screening 72 hours from the onset of the disease resolution of pneumonia
ASSESSMENT OF INSTRUMENTAL EFFICIENCY
1 Distance traveled during the 6-minute walk test on the day the pneumonia resolved
2 Spirometry will be performed on the day of screening and on the day of resolution of pneumonia and include assessment of Vital capacity Forced vital capacity Forced expiratory volume in one second Peak expiratory flow Forced expiratory flow at 25 of Forced vital capacity FVC Forced expiratory flow at 50 of FVC Forced expiratory flow at 75 of FVC
3 Chest CT scan on the day of screening after 72 hours and on the day of resolution of pneumonia with determination of localization and size of consolidation localization and size of the Ground-glass opacity air bronchograms yesno hemodynamic abnormalities yesno fluid volume in the pleural cavities
4 Cardiac ultrasound will be performed on the day of screening 72 hours later and on the day of resolution of pneumonia and will include assessment of end-diastolic end-systolic volume indexes and left ventricular ejection fraction right ventricular antero-posterior diameter right ventricular fractional area change tricuspid regurgitation velocity Tricuspid annular plane systolic excursion TAPSE tricuspid annular systolic velocity S right ventricular free wall longitudinal strain if possible diameter of the inferior vena cava and its collapse during inspiration fluid in the pericardial cavity yesno volume insignificantmoderateseveretamponade and pleural cavities
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
False
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None