Ignite Creation Date:
2024-10-26 @ 3:43 PM
Last Modification Date:
2024-10-26 @ 3:43 PM
Study NCT ID:
NCT06650384
Status:
NOT_YET_RECRUITING
Last Update Posted:
None
First Post:
2024-10-13
Brief Title:
Efficacy and Safety of N-Acetylcysteine Versus Alpha-Lipoic Acid in Colistin-Induced Nephrotoxicity
Sponsor:
None
Organization:
None
Study Overview
Official Title:
Evaluation of the Efficacy and Safety of N-Acetylcysteine Versus Alpha-Lipoic Acid on the Occurrence and Severity of Colistin-Induced Nephrotoxicity in Critically Ill Patients
Status:
NOT_YET_RECRUITING
Status Verified Date:
2024-10
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
No
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
Healthcare- associated infections that caused by multi-drug-resistant Gram-negative bacteria MDR G-ve represent the most important problem that face the critically ill patients in the ICU The available broad-spectrum antibiotics as penicillin fluoroquinolones aminoglycosides and β-lactams fail to overcome these aggressive organisms Accordingly this led to the reconsideration of old drugs such as polymyxin B and polymyxin E also known as colistin that were previously considered to be too toxic for clinical use in the treatment of MDR G-ve bacteria Colistin can be used as monotherapy or in combination with other antibiotics as high dose tigecycline carbapenem or high-dose ampicillinsulbactam
Colistin associated acute kidney injury CA-AKI is the frequently observed side effect in ICU patients treated with colistin that may lead to cessation of treatment Accordingly it is important to monitor renal functions prior to and during colistin treatment to detect the early signs of renal injury and minimize long term renal dysfunction
Inflammation with release of reactive oxygen species ROS can lead to renal tubular cells apoptosis Several animal studies proved the beneficial effect of the concomitant use of antioxidants as N-acetylcysteine alpha lipoic acid in preventing or attenuating colistin induced nephrotoxicity by their potent antioxidant effects Therefore a clinical trial will be carried out to evaluate the efficacy and safety of N-acetylcysteine versus Alpha-lipoic acid in the prevention of colistin-induced nephrotoxicity in critically ill patients
Colistin associated acute kidney injury CA-AKI is the frequently observed side effect in ICU patients treated with colistin that may lead to cessation of treatment Accordingly it is important to monitor renal functions prior to and during colistin treatment to detect the early signs of renal injury and minimize long term renal dysfunction
Inflammation with release of reactive oxygen species ROS can lead to renal tubular cells apoptosis Several animal studies proved the beneficial effect of the concomitant use of antioxidants as N-acetylcysteine alpha lipoic acid in preventing or attenuating colistin induced nephrotoxicity by their potent antioxidant effects Therefore a clinical trial will be carried out to evaluate the efficacy and safety of N-acetylcysteine versus Alpha-lipoic acid in the prevention of colistin-induced nephrotoxicity in critically ill patients
Detailed Description:
Nosocomial infections caused by multi-drug-resistant Gram-negative bacteria MDR G-ve bacteria particularly Acinetobacter baumannii Pseudomonas aeruginosa and Klebsiella pneumonia represent a crucial rapidly increasing health problem worldwide nowadays
The available effective antibiotics including broad-spectrum penicillin fluoroquinolones aminoglycosides and β-lactams carbapenems monobactam and cephalosporins often fail to combat these organisms and the pharmaceutical pipeline is still facing the problem of lack of new moieties The new and potent β-lactam β-lactamase combinations antibiotics Tigecycline and other newer highly expensive β-lactam β-lactamase combinations as ceftazidimeavibactam meropenemvaborbactam have their concerns related to their high cost and unavailability in all countries Moreover they are ineffective against Metallo-β-lactamase-producing CRE Accordingly this led to the reconsideration of old drugs such as polymyxin B and polymyxin E also known as colistin that were previously considered to be too toxic for clinical use in the treatment of MDR G-ve bacteria Colistin has re-emerged for treatment of severe infections caused by multidrug-resistant Gram-negative bacteria especially Pseudomonas aeruginosa Acinetobacter baummannii Klebsiella pneumonia and Enterobacterales Colistin monotherapy or colistin based synergistic combinations with a carbapenem high-dose ampicillinsulbactam or high dose tigecycline represent the last resort option to overcome CR-GNB in critically ill patients Colistin colistimethate sodium is the inactive prodrug that is hydrolyzed to colistin that act as a cationic detergent and disrupt the bacterial cytoplasmic membrane resulting in leak of intracellular substances and cell death
Colistin associated acute kidney injury CA-AKI is frequently observed in the intensive care unit ICU patients treated with colistin especially in patients with advanced age other comorbidities baseline renal dysfunction and hemodynamically unstable patients Colistin is primarily eliminated renally and may induce acute kidney injury at a rate of up to 53 Many studies have discussed the prevalence of colistin induced nephrotoxicity One recent study in 2023 stated that the incidence of nephrotoxicity was 449 95 CI 37 to 53 and its severity according to Kidney Disease Improving Global Outcomes KDIGO guidelines in 2012 was stage1 47 stage2 21 and stage3 31 Accordingly it is important to monitor renal functions prior to and during colistin treatment to detect the early signs of renal injury and minimize long term renal dysfunction A serum creatinine SCr is commonly used for estimation of renal function
Cockcroft-Gault equation is the most common formula for determining creatinine clearance which estimates glomerular filtration rate GFR Although creatinine clearance may over-estimate GFR by 10-20 but still remains the standard for drug dosing adjustments
Accordingly it is important to monitor renal functions prior to and during colistin treatment to detect the early signs of renal injury
Inflammation with the release of many cytokines into the renal tubular cells oxidative stress the increased release of reactive oxygen species ROS Also excessive free radical production and low antioxidant level which lead to renal tubular cells apoptosis with an effect on the mitochondria as a primary site of damage
Mechanism of colistin induced nephrotoxicity is similar to that of contrast induced nephrotoxicity the nephrotoxic effect of methotrexatecisplatin MTXCPT and vancomycin induced nephrotoxicity
In several animal studies the concomitant use of antioxidants as N-acetylcysteine alpha lipoic acid vitamin E melatonin and ascorbic acid with colistin have shown promising results in preventing or attenuating colistin induced nephrotoxicity by their potent antioxidant effects that decrease ROS levels and cellular apoptosis
NAC acts as a glutathione precursor that plays an important role in increasing the glutathione S- transferase activity that decrease the oxidative stress by neutralizing ROS Animal studies found that N-Acetylcysteine seems to have a beneficial role in the restoration of the oxidant injury caused by colistin and prevention of colistin-induced nephrotoxicity by its antioxidant effect Nevertheless one clinical study stated that N-Acetylcysteine 1200 mg day did not have any effect on the prevention of colistin-induced nephrotoxicity Double dose of N-acetylcysteine 1200 mg orally twice daily seemed to be more effective than the standard dose 600 mg orally twice daily in preventing contrast agent associated nephrotoxicity
Also the efficacy of NAC in the prevention of vancomycin induced nephrotoxicity was shown in a randomized controlled clinical trial in 2020The mechanism of colistin induced nephrotoxicity is similar to that of contrast and vancomycin Alpha-lipoic acid ALA known as thioctic acid 600 mg twice daily is an organosulfur compound found in the mitochondria It is necessary for many enzymatic functions and can prevent nephrotoxicity through its strong antioxidant properties that act as a free radical scavenger and regenerator of endogenous antioxidants Up till now only one study on rats have demonstrated that ALA is an effective strategy for alleviation of colistin induced nephrotoxicity by its strong antioxidant effect
An animal study on rats proved that the potent antioxidant Alpha-lipoic acid 10mgkg attenuated nephrotoxicity induced by MTXCPT by enhancing the activities of mitochondrial enzymes and decreasing levels of reactive oxygen species The mechanism of colistin induced nephrotoxicity is similar to that of methotrexatecisplatin
Objectives To evaluate the efficacy and safety of high dose N-acetylcysteine versus alpha-lipoic acid on the occurrence and severity of colistin-induced nephrotoxicity in critically ill patients by assessment of the following
1 Efficacy parameters
Occurrence and severity of nephrotoxicity
Clinical outcomes ICU stay mortality dose modification and need for dialysis
2 Safety parameters
Occurrence of ARDs Methodology
As per our protocol critically ill patients 18 years presenting to the critical care medicine Department-Cairo University Hospitals and initiating treatment with colistin for suspected or confirmed multi-drug-resistant Gram-negative bacterial infection per culture will be recruited
180 Eligible patients will be randomly assigned by a 111 ratio using a computer-generated sequence to any of the following 3 groups
Group1 n60 will receive IV colistin 300 mg CBA loading dose followed 12 hours later by a maintenance dose of 150-180 mg CBA twice daily based on Crcl calculated using Cockcroft -Gault equation - Group2 n60 will receive IV colistin 300mg CBA loading dose followed by a maintenance dose of 150-180 mg CBA twice daily based on Crcl calculated using Cockcroft -Gault equation in addition to enteral sachets of N-acetyl cysteine 1200 mg twiceday acetylcysteine 600mg sachets produced by South Egypt Drug Industries Company SEDICO
Group3 n60 will receive IV colistin 300mg CBA loading dose followed by a maintenance dose 150-180 mg CBA twice daily based on Crcl calculated using Cockcroft -Gault equation in addition to enteral Alpha-lipoic acid 600mg twice daily thiotacid 600mg produced by EVA PHARM before meals
Every patient in the study will be subjected to the following
1 Data collection
Data will be collected at baseline and at regular intervals from patients medical files for all groups and this includes
1 Patients demographic gender age weight Histories social medications and pre-existing comorbid conditions and source of infection
b Severity scores for illness evaluation baseline and at the end Acute Physiology and Chronic Health Evaluation II APACHE II score Sequential Organ Failure Assessment SOFA score c- All culture results and susceptibilities d-The use of other potentially nephrotoxic drugs will be recorded 2- Laboratory evaluation will be done initially and every other day up to the end of the duration of colistin treatment in the 3 groups for the following Complete blood count CBC including total leucocytic count TLC hemoglobin Hgb platelets PLT count inflammatory markers C- reactive protein urine output UOP renal functions BUN SCr Crcl that can be predicted from serum creatinine value using Cockcroft-Gault equation
3- Vital signs assessments including blood pressure heart rate temperature at baseline and every other day till the end of colistin therapy 4- Clinical outcomes evaluation
-Assessment of Colistin Induced nephrotoxicity
All patients in the 3 groups will be assessed daily for the occurrence and severity of colistin induced nephrotoxicity defined by the KIDIGO 2012 as
Definition of Colistin induced Nephrotoxicity according to KDIGO staging 2012
Moreover the following will be reported for all patients
- Average dose of colistin used daily during the duration of its use Average duration of colistin use according to the type of infection and the clinical response
-Other clinical outcomes 5 Total length of ICU stays 6 Need for dose modification according to creatinine clearance 7 Need for hemodialysis 8 Mortality 4 Safety assessment All adverse drug reactions will be monitored and reported for the 3 groups
The available effective antibiotics including broad-spectrum penicillin fluoroquinolones aminoglycosides and β-lactams carbapenems monobactam and cephalosporins often fail to combat these organisms and the pharmaceutical pipeline is still facing the problem of lack of new moieties The new and potent β-lactam β-lactamase combinations antibiotics Tigecycline and other newer highly expensive β-lactam β-lactamase combinations as ceftazidimeavibactam meropenemvaborbactam have their concerns related to their high cost and unavailability in all countries Moreover they are ineffective against Metallo-β-lactamase-producing CRE Accordingly this led to the reconsideration of old drugs such as polymyxin B and polymyxin E also known as colistin that were previously considered to be too toxic for clinical use in the treatment of MDR G-ve bacteria Colistin has re-emerged for treatment of severe infections caused by multidrug-resistant Gram-negative bacteria especially Pseudomonas aeruginosa Acinetobacter baummannii Klebsiella pneumonia and Enterobacterales Colistin monotherapy or colistin based synergistic combinations with a carbapenem high-dose ampicillinsulbactam or high dose tigecycline represent the last resort option to overcome CR-GNB in critically ill patients Colistin colistimethate sodium is the inactive prodrug that is hydrolyzed to colistin that act as a cationic detergent and disrupt the bacterial cytoplasmic membrane resulting in leak of intracellular substances and cell death
Colistin associated acute kidney injury CA-AKI is frequently observed in the intensive care unit ICU patients treated with colistin especially in patients with advanced age other comorbidities baseline renal dysfunction and hemodynamically unstable patients Colistin is primarily eliminated renally and may induce acute kidney injury at a rate of up to 53 Many studies have discussed the prevalence of colistin induced nephrotoxicity One recent study in 2023 stated that the incidence of nephrotoxicity was 449 95 CI 37 to 53 and its severity according to Kidney Disease Improving Global Outcomes KDIGO guidelines in 2012 was stage1 47 stage2 21 and stage3 31 Accordingly it is important to monitor renal functions prior to and during colistin treatment to detect the early signs of renal injury and minimize long term renal dysfunction A serum creatinine SCr is commonly used for estimation of renal function
Cockcroft-Gault equation is the most common formula for determining creatinine clearance which estimates glomerular filtration rate GFR Although creatinine clearance may over-estimate GFR by 10-20 but still remains the standard for drug dosing adjustments
Accordingly it is important to monitor renal functions prior to and during colistin treatment to detect the early signs of renal injury
Inflammation with the release of many cytokines into the renal tubular cells oxidative stress the increased release of reactive oxygen species ROS Also excessive free radical production and low antioxidant level which lead to renal tubular cells apoptosis with an effect on the mitochondria as a primary site of damage
Mechanism of colistin induced nephrotoxicity is similar to that of contrast induced nephrotoxicity the nephrotoxic effect of methotrexatecisplatin MTXCPT and vancomycin induced nephrotoxicity
In several animal studies the concomitant use of antioxidants as N-acetylcysteine alpha lipoic acid vitamin E melatonin and ascorbic acid with colistin have shown promising results in preventing or attenuating colistin induced nephrotoxicity by their potent antioxidant effects that decrease ROS levels and cellular apoptosis
NAC acts as a glutathione precursor that plays an important role in increasing the glutathione S- transferase activity that decrease the oxidative stress by neutralizing ROS Animal studies found that N-Acetylcysteine seems to have a beneficial role in the restoration of the oxidant injury caused by colistin and prevention of colistin-induced nephrotoxicity by its antioxidant effect Nevertheless one clinical study stated that N-Acetylcysteine 1200 mg day did not have any effect on the prevention of colistin-induced nephrotoxicity Double dose of N-acetylcysteine 1200 mg orally twice daily seemed to be more effective than the standard dose 600 mg orally twice daily in preventing contrast agent associated nephrotoxicity
Also the efficacy of NAC in the prevention of vancomycin induced nephrotoxicity was shown in a randomized controlled clinical trial in 2020The mechanism of colistin induced nephrotoxicity is similar to that of contrast and vancomycin Alpha-lipoic acid ALA known as thioctic acid 600 mg twice daily is an organosulfur compound found in the mitochondria It is necessary for many enzymatic functions and can prevent nephrotoxicity through its strong antioxidant properties that act as a free radical scavenger and regenerator of endogenous antioxidants Up till now only one study on rats have demonstrated that ALA is an effective strategy for alleviation of colistin induced nephrotoxicity by its strong antioxidant effect
An animal study on rats proved that the potent antioxidant Alpha-lipoic acid 10mgkg attenuated nephrotoxicity induced by MTXCPT by enhancing the activities of mitochondrial enzymes and decreasing levels of reactive oxygen species The mechanism of colistin induced nephrotoxicity is similar to that of methotrexatecisplatin
Objectives To evaluate the efficacy and safety of high dose N-acetylcysteine versus alpha-lipoic acid on the occurrence and severity of colistin-induced nephrotoxicity in critically ill patients by assessment of the following
1 Efficacy parameters
Occurrence and severity of nephrotoxicity
Clinical outcomes ICU stay mortality dose modification and need for dialysis
2 Safety parameters
Occurrence of ARDs Methodology
As per our protocol critically ill patients 18 years presenting to the critical care medicine Department-Cairo University Hospitals and initiating treatment with colistin for suspected or confirmed multi-drug-resistant Gram-negative bacterial infection per culture will be recruited
180 Eligible patients will be randomly assigned by a 111 ratio using a computer-generated sequence to any of the following 3 groups
Group1 n60 will receive IV colistin 300 mg CBA loading dose followed 12 hours later by a maintenance dose of 150-180 mg CBA twice daily based on Crcl calculated using Cockcroft -Gault equation - Group2 n60 will receive IV colistin 300mg CBA loading dose followed by a maintenance dose of 150-180 mg CBA twice daily based on Crcl calculated using Cockcroft -Gault equation in addition to enteral sachets of N-acetyl cysteine 1200 mg twiceday acetylcysteine 600mg sachets produced by South Egypt Drug Industries Company SEDICO
Group3 n60 will receive IV colistin 300mg CBA loading dose followed by a maintenance dose 150-180 mg CBA twice daily based on Crcl calculated using Cockcroft -Gault equation in addition to enteral Alpha-lipoic acid 600mg twice daily thiotacid 600mg produced by EVA PHARM before meals
Every patient in the study will be subjected to the following
1 Data collection
Data will be collected at baseline and at regular intervals from patients medical files for all groups and this includes
1 Patients demographic gender age weight Histories social medications and pre-existing comorbid conditions and source of infection
b Severity scores for illness evaluation baseline and at the end Acute Physiology and Chronic Health Evaluation II APACHE II score Sequential Organ Failure Assessment SOFA score c- All culture results and susceptibilities d-The use of other potentially nephrotoxic drugs will be recorded 2- Laboratory evaluation will be done initially and every other day up to the end of the duration of colistin treatment in the 3 groups for the following Complete blood count CBC including total leucocytic count TLC hemoglobin Hgb platelets PLT count inflammatory markers C- reactive protein urine output UOP renal functions BUN SCr Crcl that can be predicted from serum creatinine value using Cockcroft-Gault equation
3- Vital signs assessments including blood pressure heart rate temperature at baseline and every other day till the end of colistin therapy 4- Clinical outcomes evaluation
-Assessment of Colistin Induced nephrotoxicity
All patients in the 3 groups will be assessed daily for the occurrence and severity of colistin induced nephrotoxicity defined by the KIDIGO 2012 as
Definition of Colistin induced Nephrotoxicity according to KDIGO staging 2012
Moreover the following will be reported for all patients
- Average dose of colistin used daily during the duration of its use Average duration of colistin use according to the type of infection and the clinical response
-Other clinical outcomes 5 Total length of ICU stays 6 Need for dose modification according to creatinine clearance 7 Need for hemodialysis 8 Mortality 4 Safety assessment All adverse drug reactions will be monitored and reported for the 3 groups
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None