Ignite Creation Date:
2024-05-06 @ 6:29 PM
Last Modification Date:
2024-10-26 @ 2:49 PM
Study NCT ID:
NCT05677555
Status:
RECRUITING
Last Update Posted:
2023-01-10
First Post:
2022-09-10
Brief Title:
Colchicine and Inflammation in Hemodialysis Patients
Sponsor:
Assaf-Harofeh Medical Center
Organization:
Assaf-Harofeh Medical Center
Study Overview
Official Title:
Colchicine Influence on Chronic Inflammation in Hemodialysis Patients
Status:
RECRUITING
Status Verified Date:
2022-12
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:
CICI-HP
Brief Summary:
Chronic low-grade inflammation is regarded as a common comorbid condition in chronic dialysis patients
Increased inflammatory markers in chronic dialysis patients are associated with adverse clinical outcomes
Considering the association of low-grade inflammation with high rate of morbidity and mortality we decided to evaluate the anti inflammatory effect of colchicine on inflammatory markers in hemodialysis patients
Increased inflammatory markers in chronic dialysis patients are associated with adverse clinical outcomes
Considering the association of low-grade inflammation with high rate of morbidity and mortality we decided to evaluate the anti inflammatory effect of colchicine on inflammatory markers in hemodialysis patients
Detailed Description:
Adult end-stage kidney disease ESKD patients undergoing maintenance hemodialysis MHD experience high mortality and morbidity with diminished quality of life Death and hospitalization rates in MHD patients correlate strongly with indicators of chronic inflammation
Chronic low-grade inflammation is regarded as a common comorbid condition in CKD and particularly in chronic dialysis patientsSeveral circulating markers are commonly assessed as indicators of systemic inflammation IL-1 is a pro-inflammatory mediator of both acute and chronic inflammation and induces synthesis and expression of hundreds of secondary inflammatory mediators IL-1β is the main form of circulating IL-1 and is initially synthesized as a precursor pro-IL-1β that becomes activated in the setting of a macromolecular structure known as the inflammasome which is activated in CKD and perpetuates the inflammatory response IL-6 is a pro-inflammatory cytokine that promotes inflammatory events through activation and proliferation of lymphocytes differentiation of B cells leukocyte recruitment and induction of the acute-phase protein response in the liver IL-6 can be induced by IL-1 and by TNF-α the latter of which is a soluble receptor primarily produced by monocytes and macrophages and elevated in states of chronic inflammation CRP is an acute phase reactant downstream from IL-6 and is a more specific marker of plaque vulnerability and risk of cardiovascular events with data suggesting it may play a direct role in atherogenesis rather than simply acting as a marker as previously believed
Increased inflammatory markers in chronic dialysis patients are associated with adverse clinical outcomes including all-cause mortality cardiovascular events protein energy wasting and diminished motor function cognitive impairment as well as other adverse consequences including CKD-mineral and bone disorder CKD-MBD anemia and insulin resistance
Despite the strong evidence that the prevalence of chronic inflammation is high and it independently predicts numerous adverse clinical outcomes in chronic dialysis patients the evidence for a role of inflammation in affecting outcomes is limited by the fact that most of the available evidence is epidemiological in nature with some additional support provided by mechanistic animal studies Strategies shown to reduce systemic inflammatory markers in chronic kidney disease andor chronic dialysis patients include pharmacological and non-pharmacological approaches Pharmacological strategies that have been evaluated are specific anti-cytokine therapies anakinra as well as IL-6 monoclonal antibody etc as well as non-specific agents with anti-inflammatory properties including statins angiotensin converting enzyme inhibitors and angiotensin receptor blockers cholecalciferol vit D sevelamer peroxisome proliferator-activated receptor-γ PPAR-γ agonists and growth hormone However the data that reducing systemic inflammation improves clinical outcomes are currently lacking this area represents an important future research direction
Colchicine is an ancient medication that is currently approved for the treatment of gout and FMF However colchicine has a wide range of anti-inflammatory activities and studies indicate that it may be beneficial in a variety of other conditions In this respect attention should be paid to the recently published article that shows that colchicine at a dose of 05 mg daily led to a reduction of inflammation expressed by serum CRP levels and a significantly lower risk of ischemic cardiovascular events than placebo among patients with a recent myocardial infarction Interestingly although acute preprocedural administration of colchicine did not lower the risk of percutaneous coronary intervention PCI-related myocardial injury it successfully attenuated the increase in interleukin-6 and high-sensitivity C-reactive protein concentrations after PCI when compared with placebo Recently reported that short-term administration of low-dose colchicine significantly alleviated endothelial inflammation with reduction of serum CRP concentration in coronary artery disease patients It was found that short-term colchicine therapy dramatically reduced the expression levels of IL-1β IL-6 and IL-18 by blockade of nucleotide-binding oligomerization domain-like receptors pyrin domain-containing 3 NLRP3 inflammasome activation in acute coronary syndrome patients
The only paper reported on the use of colchicine in dialysis patients is the report on the use of colchicine in peritoneal dialysis PD rats with encapsulating peritoneal sclerosis There is no information in the literature on whether colchicine affects inflammation measures in dialysis patients Given the high morbidity and mortality in MHD patients targeting inflammation represents a potentially novel and attractive strategy if it can indeed be shown to improve their adverse outcomes
Considering the association of low-grade inflammation with high rate of morbidity and mortality in MHD population and anti-inflammatory potential of colchicine on the other hand we decided to conduct the Colchicine Influence on Chronic Inflammation in Hemodialysis Patients CICI-HP study to evaluate the effects of colchicine on inflammatory markers as well as its safety profile in MHD patients
The study will be conducted as a 3-month double-blind parallel-group placebo-controlled single center study The study population will include 50 ESKD patients receiving MHD treatment with different degrees of low-grade inflammation defined as plasma CRP above 10 mgL and below 100 mgL A total of 50 subjects will be randomized to treatment with either colchicine 05 mg three times a week at the end of each hemodialysis session or matching placebo Both patients and investigators including doctors nurses and dietitians will be blinded to group assignment Randomization codes will conceal until end of trial The randomization list and all study products will be provided by Super Pharm Professional laboratory Petah Tikva
After meeting all inclusion criteria all study participants will be seen at 4 visits over the 3 month period All visits will take place in connection with a regular dialysis session At all study visits predialysis blood samples will be collected in a fasting state from each study patient The dietary energy and protein intake will be calculated and normalized for ideal body weight according to the European Best Practice Guidelines by skilled dietitian Dietitian records based on self-completed food diaries with continuous 3-day dietary histories including a dialysis day a weekend day and a non-dialysis day will be used to calculate the dietary intake The same dietitian will perform all anthropometric measurements and calculation of daily calorie and protein intake per diaries records During the dialysis session SNAQ questionnaires for appetite assessment will be filled out At study entry each participant will be instructed how to work with questionnaires All participants will also fill out the EQ-5D questionnaires on their own or will be assisted by an independent person if the patient himself unable to complete questionnaire Handgrip strength HGS will be measured in all patients using the non-dominant hand The patients will undergo BIA at approximately 30-minutes postdialysis
The study parameters will be SNAQ the simplified nutritional appetite questionnaire for appetite assessment daily energy and protein intake for dietary assessment EQ-5D for health-related QoL assessment biochemical nutritional markers serum albumin creatinine transferrin uric acid lipid profile IGF-1 appetite-regulating peptides leptin acyl-ghrelin obestatin NPY inflammatory biochemical mediators CRP neutrophil-to-lymphocyte ratio IL-6 and TNFα handgrip strength as functional assessment of muscle mass anthropometric parameters body weight BMI skinfold thickness mid arm circumference and mid arm circumference calculated lean body mass fat mass fat free mass phase angle measured by BIA malnutrition inflammation score geriatric nutritional risk index GNRI and objective score of nutrition on dialysis OSND as quantitative assessment of nutritional status
All patients will undergo regular hemodialysis via their vascular access 4-5 h 3-4 times per week at a blood flow rate 250-300 mLmin Bicarbonate dialysate 30 mEqL at a dialysis solution flow rate of 500 mLmin will be used in all cases All patients will use the same high flux dialyser membrane biocompatible with surface area of 18-22m2 and patients wont use re-used dialyzer membrane The efficiency of the dialysis will be assessed based on the delivered dose of dialysis KtVurea using a single-pool urea kinetic model Protein equivalent of nitrogen appearance nPNA an indirect indicator of protein intake will be calculated from serum urea levels using three-point method
During the study period from screening to the last follow up visit - about 3 months period we will monitor all morbid events for all study patients Specific causes of hospitalization grouped as infectious causes cardiac causes vascular-access related causes and other causes classified according to ICD-9 codes will be recorded
Chronic low-grade inflammation is regarded as a common comorbid condition in CKD and particularly in chronic dialysis patientsSeveral circulating markers are commonly assessed as indicators of systemic inflammation IL-1 is a pro-inflammatory mediator of both acute and chronic inflammation and induces synthesis and expression of hundreds of secondary inflammatory mediators IL-1β is the main form of circulating IL-1 and is initially synthesized as a precursor pro-IL-1β that becomes activated in the setting of a macromolecular structure known as the inflammasome which is activated in CKD and perpetuates the inflammatory response IL-6 is a pro-inflammatory cytokine that promotes inflammatory events through activation and proliferation of lymphocytes differentiation of B cells leukocyte recruitment and induction of the acute-phase protein response in the liver IL-6 can be induced by IL-1 and by TNF-α the latter of which is a soluble receptor primarily produced by monocytes and macrophages and elevated in states of chronic inflammation CRP is an acute phase reactant downstream from IL-6 and is a more specific marker of plaque vulnerability and risk of cardiovascular events with data suggesting it may play a direct role in atherogenesis rather than simply acting as a marker as previously believed
Increased inflammatory markers in chronic dialysis patients are associated with adverse clinical outcomes including all-cause mortality cardiovascular events protein energy wasting and diminished motor function cognitive impairment as well as other adverse consequences including CKD-mineral and bone disorder CKD-MBD anemia and insulin resistance
Despite the strong evidence that the prevalence of chronic inflammation is high and it independently predicts numerous adverse clinical outcomes in chronic dialysis patients the evidence for a role of inflammation in affecting outcomes is limited by the fact that most of the available evidence is epidemiological in nature with some additional support provided by mechanistic animal studies Strategies shown to reduce systemic inflammatory markers in chronic kidney disease andor chronic dialysis patients include pharmacological and non-pharmacological approaches Pharmacological strategies that have been evaluated are specific anti-cytokine therapies anakinra as well as IL-6 monoclonal antibody etc as well as non-specific agents with anti-inflammatory properties including statins angiotensin converting enzyme inhibitors and angiotensin receptor blockers cholecalciferol vit D sevelamer peroxisome proliferator-activated receptor-γ PPAR-γ agonists and growth hormone However the data that reducing systemic inflammation improves clinical outcomes are currently lacking this area represents an important future research direction
Colchicine is an ancient medication that is currently approved for the treatment of gout and FMF However colchicine has a wide range of anti-inflammatory activities and studies indicate that it may be beneficial in a variety of other conditions In this respect attention should be paid to the recently published article that shows that colchicine at a dose of 05 mg daily led to a reduction of inflammation expressed by serum CRP levels and a significantly lower risk of ischemic cardiovascular events than placebo among patients with a recent myocardial infarction Interestingly although acute preprocedural administration of colchicine did not lower the risk of percutaneous coronary intervention PCI-related myocardial injury it successfully attenuated the increase in interleukin-6 and high-sensitivity C-reactive protein concentrations after PCI when compared with placebo Recently reported that short-term administration of low-dose colchicine significantly alleviated endothelial inflammation with reduction of serum CRP concentration in coronary artery disease patients It was found that short-term colchicine therapy dramatically reduced the expression levels of IL-1β IL-6 and IL-18 by blockade of nucleotide-binding oligomerization domain-like receptors pyrin domain-containing 3 NLRP3 inflammasome activation in acute coronary syndrome patients
The only paper reported on the use of colchicine in dialysis patients is the report on the use of colchicine in peritoneal dialysis PD rats with encapsulating peritoneal sclerosis There is no information in the literature on whether colchicine affects inflammation measures in dialysis patients Given the high morbidity and mortality in MHD patients targeting inflammation represents a potentially novel and attractive strategy if it can indeed be shown to improve their adverse outcomes
Considering the association of low-grade inflammation with high rate of morbidity and mortality in MHD population and anti-inflammatory potential of colchicine on the other hand we decided to conduct the Colchicine Influence on Chronic Inflammation in Hemodialysis Patients CICI-HP study to evaluate the effects of colchicine on inflammatory markers as well as its safety profile in MHD patients
The study will be conducted as a 3-month double-blind parallel-group placebo-controlled single center study The study population will include 50 ESKD patients receiving MHD treatment with different degrees of low-grade inflammation defined as plasma CRP above 10 mgL and below 100 mgL A total of 50 subjects will be randomized to treatment with either colchicine 05 mg three times a week at the end of each hemodialysis session or matching placebo Both patients and investigators including doctors nurses and dietitians will be blinded to group assignment Randomization codes will conceal until end of trial The randomization list and all study products will be provided by Super Pharm Professional laboratory Petah Tikva
After meeting all inclusion criteria all study participants will be seen at 4 visits over the 3 month period All visits will take place in connection with a regular dialysis session At all study visits predialysis blood samples will be collected in a fasting state from each study patient The dietary energy and protein intake will be calculated and normalized for ideal body weight according to the European Best Practice Guidelines by skilled dietitian Dietitian records based on self-completed food diaries with continuous 3-day dietary histories including a dialysis day a weekend day and a non-dialysis day will be used to calculate the dietary intake The same dietitian will perform all anthropometric measurements and calculation of daily calorie and protein intake per diaries records During the dialysis session SNAQ questionnaires for appetite assessment will be filled out At study entry each participant will be instructed how to work with questionnaires All participants will also fill out the EQ-5D questionnaires on their own or will be assisted by an independent person if the patient himself unable to complete questionnaire Handgrip strength HGS will be measured in all patients using the non-dominant hand The patients will undergo BIA at approximately 30-minutes postdialysis
The study parameters will be SNAQ the simplified nutritional appetite questionnaire for appetite assessment daily energy and protein intake for dietary assessment EQ-5D for health-related QoL assessment biochemical nutritional markers serum albumin creatinine transferrin uric acid lipid profile IGF-1 appetite-regulating peptides leptin acyl-ghrelin obestatin NPY inflammatory biochemical mediators CRP neutrophil-to-lymphocyte ratio IL-6 and TNFα handgrip strength as functional assessment of muscle mass anthropometric parameters body weight BMI skinfold thickness mid arm circumference and mid arm circumference calculated lean body mass fat mass fat free mass phase angle measured by BIA malnutrition inflammation score geriatric nutritional risk index GNRI and objective score of nutrition on dialysis OSND as quantitative assessment of nutritional status
All patients will undergo regular hemodialysis via their vascular access 4-5 h 3-4 times per week at a blood flow rate 250-300 mLmin Bicarbonate dialysate 30 mEqL at a dialysis solution flow rate of 500 mLmin will be used in all cases All patients will use the same high flux dialyser membrane biocompatible with surface area of 18-22m2 and patients wont use re-used dialyzer membrane The efficiency of the dialysis will be assessed based on the delivered dose of dialysis KtVurea using a single-pool urea kinetic model Protein equivalent of nitrogen appearance nPNA an indirect indicator of protein intake will be calculated from serum urea levels using three-point method
During the study period from screening to the last follow up visit - about 3 months period we will monitor all morbid events for all study patients Specific causes of hospitalization grouped as infectious causes cardiac causes vascular-access related causes and other causes classified according to ICD-9 codes will be recorded
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?:
False
Is an FDA AA801 Violation?:
None