Ignite Creation Date:
2024-05-05 @ 5:07 PM
Last Modification Date:
2024-10-26 @ 9:28 AM
Study NCT ID:
NCT00390247
Status:
WITHDRAWN
Last Update Posted:
2016-02-09
First Post:
2006-10-18
Brief Title:
Thalidomide for the Treatment of Malnutrition Inflammation Syndrome in Peritoneal Dialysis Patients
Sponsor:
Chinese University of Hong Kong
Organization:
Chinese University of Hong Kong
Study Overview
Official Title:
Thalidomide for the Treatment of Malnutrition Inflammation Syndrome in Peritoneal Dialysis Patients A Randomized Control Trial
Status:
WITHDRAWN
Status Verified Date:
2007-04
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Fail of applying funding
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
Hypothesis In peritoneal dialysis PD patients malnutrition inflammation and atherosclerotic cardiovascular disease commonly coexist The triad has been coined the MIA syndrome Proinflammatory cytokines such as tumor necrosis factor-alpha TNF-alpha plays a central role in the pathogenesis of the MIA syndrome Thalidomide selectively inhibits the production of TNF-alpha and represents a valuable anti-cytokine therapy
Specific Aim To study the effect of thalidomide in attenuating or reversing malnutrition and systemic inflammation in PD patients
Research Plan
Design Double-blinded randomised prospective placebo control trial Setting Renal unit of a university teaching hospital Subjects Sixty prevalent PD patients with evidence of malnutrition Interventions Patients will be randomised to receive either oral thalidomide 100 mg nocte or placebo
Main outcome measures Patients will be followed for 1 year Nutritional parameters including serum albumin subjective global assessment malnutrition-inflammation score normalised protein nitrogen appearance fat-free edema-free body mass and anthropometry measurements will be monitored Systemic inflammatory markers such as serum C-reactive protein and IL-6 will be assayed Hospitalisation cardiovascular events and overall patient survival will also be compared during study period
Expected Outcome
Nutritional parameters and markers of systemic inflammation are expected to improve with thalidomide therapy The magnitude of improvement in nutrition as well as patient morbidity will be compared with placebo
In Hong Kong 80 of end-stage renal failure patients are treated with PD Malnutrition cardiovascular disease and systemic inflammatory response are all common in our clinical practice They are major causes of patient morbidity and mortality As a readily available anti-cytokine therapy thalidomide may represent a valuable treatment of the MIA syndrome The proposed study will provide important insight on the clinical benefit of thalidomide treatment in malnourished PD patients which accounts for about one-third of our dialysis population
Specific Aim To study the effect of thalidomide in attenuating or reversing malnutrition and systemic inflammation in PD patients
Research Plan
Design Double-blinded randomised prospective placebo control trial Setting Renal unit of a university teaching hospital Subjects Sixty prevalent PD patients with evidence of malnutrition Interventions Patients will be randomised to receive either oral thalidomide 100 mg nocte or placebo
Main outcome measures Patients will be followed for 1 year Nutritional parameters including serum albumin subjective global assessment malnutrition-inflammation score normalised protein nitrogen appearance fat-free edema-free body mass and anthropometry measurements will be monitored Systemic inflammatory markers such as serum C-reactive protein and IL-6 will be assayed Hospitalisation cardiovascular events and overall patient survival will also be compared during study period
Expected Outcome
Nutritional parameters and markers of systemic inflammation are expected to improve with thalidomide therapy The magnitude of improvement in nutrition as well as patient morbidity will be compared with placebo
In Hong Kong 80 of end-stage renal failure patients are treated with PD Malnutrition cardiovascular disease and systemic inflammatory response are all common in our clinical practice They are major causes of patient morbidity and mortality As a readily available anti-cytokine therapy thalidomide may represent a valuable treatment of the MIA syndrome The proposed study will provide important insight on the clinical benefit of thalidomide treatment in malnourished PD patients which accounts for about one-third of our dialysis population
Detailed Description:
Overall study design
This is a single-center randomized placebo control study on 60 prevalent PD patients
Recruitment phase will take up to 12 months and the study phase will be 1 year Study code will only be revealed at the end of the study period or if patients develop serious adverse reactions
Patient selection
A randomized prospective study will be performed in 60 stable PD patients Recruitment criteria are
A clinically stable adult patients 18 to 80 years old on PD and
B evidence of malnutrition
1 overall subjective global assessment score 5 or
2 malnutrition inflammation score 9 or
3 serum albumin 35 gL C written patient informed consent
Exclusion criteria are
Patients who are planned to have elective living donor transplant within 6 months Patients who are planned to transfer to other renal center within 6 months High likelihood of early withdrawal from the study eg myocardial infarction severe or unstable coronary disease stroke severe liver disease within 3 months Active infection or systemic inflammatory disease Current malignant disease Pregnancy or breast-feeding Women of childbearing potential with unreliable birth control methods Known hypersensitivity to thalidomide
Baseline data including age sex underlying renal disease presence of diabetes hepatitis B status requirement of helper for dialysis procedure PD regimen and duration on dialysis are recorded
Interventions
After initial evaluation in a screening visit at -4 week patients will be randomly assigned to receive either oral thalidomide 100 mg nocte or placebo Thalidomide will be obtained from Penn Pharmaceuticals Ltd Gwent UK as 100 mg tablets and prescribed in accordance with the published guidelines for the clinical use and dispensing of thalidomide 34 There will be 30 patients on each arm of randomization Dialysis prescription will be changed only if there is clinical evidence of underdialysis Both patients and investigators will be blinded from the therapy during follow up assessment Side effects will be recorded and the drug will be discontinued when clinically necessary
Clinical follow up
Patients will be followed at at -4 screening 0 4 8 12 18 24 30 36 44 and 52 weeks The following clinical data will be documented during each visit
Body height and body weight Blood pressure Compliance to thalidomide by pill count Compliance to dialysis exchange by direct questioning Skin itchiness score from 0 to 3 as described previously 31
Body-mass index and body surface area will be computed The majority of patients will be on three or four 2-liter exchanges per day Blood pressure or edema are controlled with standard anti-hypertensive agents andor hypertonic dialysate
Laboratory parameters
A full panel of biochemical parameters will be monitored
Hemoglobin plasma sodium potassium urea creatinine albumin calcium phosphate alkaline phosphatase and alanine transaminase at -4 0 4 8 12 18 24 30 36 44 and 52 weeks Fasting serum glucose lipid and iron profile at 0 24 and 52 weeks Serum parathyroid hormone at 0 and 52 weeks Serum inflammatory markers at 0 12 24 36 and 52 weeks
Inflammatory markers include serum C-reactive protein CRP interleukin-6 IL-6 leptin adiponectin tumor necrosis factor alpha TNF-alpha and fibrinogen levels as suggested by other groups 35-38
Nutritional assessment
Nutritional status will assessed by subjective global assessment SGA comprehensive malnutrition-inflammation score MIS normalized protein nitrogen appearance NPNA serum albumin level anthropometric lean body mass LBM and fat-free edema-free body mass FEBM
SGA will be performed at -4 0 12 24 36 and 52 weeks by a single observer The 4-item 7-point scoring system proposed by Enia et al 39 will be used MIS will be performed at -4 0 12 24 36 and 52 weeks The calculation of MIS has been described previously 40 Briefly MIS consists of 4 main parts and 10 components all scored from 0 normal to 3 very severe The total score ranges from 0 to 30
FEBM and PNA will be measured by creatinine kinetics at 0 24 and 52 weeks A 24-hour dialysate and urine collections will be performed Total and peritoneal KtV are determined by standard methods Residual GFR is calculated as average of 24-hour urinary urea and creatinine clearance FEBM is calculated according to the formula of Forbes and Brunining 41 PNA is derived from the Randersons formula 42 It is further normalized to standard body weight
Anthropometric measurements will be performed at 0 12 24 36 and 52 weeks by a single observer This include bicep tricep subscapular and supra-iliac skin fold thickness and midarm muscle circumference Derived variables by anthropometric measurements including lean body mass LBM and percentage of body fat will be computed by standard formula 43
Pulse wave velocity
Pulse wave velocity PWV an index of aortic stiffness is measured using an automatic computerized recorder at 0 24 and 52 weeks The results will be analyzed by the Complior SP program Artech Medical France Briefly pressure-sensitive transducers are placed over the neck carotid artery wrist radial artery and groin femoral artery with the patient in the supine position on day of haemodialysis treatment before putting patient to the dialysis machine PWV of the carotid-femoral and carotid-radial territory is calculated by dividing the distance between the sensors by the time corresponding to the period separating the start of the rising phase of the carotid pulse wave and that of the femoral and also the radial pulse waves The procedure takes 10 to15 seconds to complete The test will be performed by the same observer to eliminate effect of intra-observer variation
Health-related quality of life
Patient acceptance and satisfaction will be assessed by the Chinese translation of Kidney Disease Quality of Life Short Form KDQOL-SFTM version 13 at 0 and 52 weeks
Outcome
The major outcome measure is nutritional status as detailed above The schedule of various tests is summarized in Appendix 2 Secondary outcomes include the followings
Change in arterial pulse wave velocity Total number of days of hospital admission during study period Composite cardiovascular end point cardiovascular death non-fatal myocardial infarction or stroke hospital admission for unstable angina coronary intervention transient ischemic attack or lower limb ischemia Number of episode of peritonitis during study period All cause mortality
Transplantation conversion to hemodialysis recovery of renal function and transfer out of the unit will also be recorded
4 Potential Outcomes
In Hong Kong 80 of end-stage renal failure patients are treated with peritoneal dialysis PD In 2004 there were over 3000 PD patients in Hong Kong Malnutrition cardiovascular disease and systemic inflammatory state are all common in our clinical practice They are major causes of patient morbidity and mortality The financial implication is considerable
As a readily available anti-cytokine therapy thalidomide may represent a valuable treatment of the MIA syndrome The proposed study will provide important insight on the clinical benefit of thalidomide treatment in malnourished PD patients which accounts for about one-third of our dialysis population
Data Analysis
Statistical analysis will be performed by SPSS for Windows software version 115 SPSS Inc Chicago IL All data will be expressed in mean - standard deviation unless otherwise specified Serial changes of nutritional parameters dialysis adequacy and inflammatory markers will be compared to the baseline values by analysis of variance for multiple measures MANOVA Serial change in residual GFR is examined by Wilcoxons rank sum test with Bonferronis correction for multiple comparison because of skewed data Nutritional status and systemic inflammatory markers after one year will be compared between the 2 groups by Students t-test for parametric data Hospitalization and peritonitis rate between the groups are compared by Kruskal-Wallis test because the data will be highly skewed Actuarial patient survival will be compared by logrank test with Kaplan-Meier survival curves and treatment group as stratifying variable
This is a single-center randomized placebo control study on 60 prevalent PD patients
Recruitment phase will take up to 12 months and the study phase will be 1 year Study code will only be revealed at the end of the study period or if patients develop serious adverse reactions
Patient selection
A randomized prospective study will be performed in 60 stable PD patients Recruitment criteria are
A clinically stable adult patients 18 to 80 years old on PD and
B evidence of malnutrition
1 overall subjective global assessment score 5 or
2 malnutrition inflammation score 9 or
3 serum albumin 35 gL C written patient informed consent
Exclusion criteria are
Patients who are planned to have elective living donor transplant within 6 months Patients who are planned to transfer to other renal center within 6 months High likelihood of early withdrawal from the study eg myocardial infarction severe or unstable coronary disease stroke severe liver disease within 3 months Active infection or systemic inflammatory disease Current malignant disease Pregnancy or breast-feeding Women of childbearing potential with unreliable birth control methods Known hypersensitivity to thalidomide
Baseline data including age sex underlying renal disease presence of diabetes hepatitis B status requirement of helper for dialysis procedure PD regimen and duration on dialysis are recorded
Interventions
After initial evaluation in a screening visit at -4 week patients will be randomly assigned to receive either oral thalidomide 100 mg nocte or placebo Thalidomide will be obtained from Penn Pharmaceuticals Ltd Gwent UK as 100 mg tablets and prescribed in accordance with the published guidelines for the clinical use and dispensing of thalidomide 34 There will be 30 patients on each arm of randomization Dialysis prescription will be changed only if there is clinical evidence of underdialysis Both patients and investigators will be blinded from the therapy during follow up assessment Side effects will be recorded and the drug will be discontinued when clinically necessary
Clinical follow up
Patients will be followed at at -4 screening 0 4 8 12 18 24 30 36 44 and 52 weeks The following clinical data will be documented during each visit
Body height and body weight Blood pressure Compliance to thalidomide by pill count Compliance to dialysis exchange by direct questioning Skin itchiness score from 0 to 3 as described previously 31
Body-mass index and body surface area will be computed The majority of patients will be on three or four 2-liter exchanges per day Blood pressure or edema are controlled with standard anti-hypertensive agents andor hypertonic dialysate
Laboratory parameters
A full panel of biochemical parameters will be monitored
Hemoglobin plasma sodium potassium urea creatinine albumin calcium phosphate alkaline phosphatase and alanine transaminase at -4 0 4 8 12 18 24 30 36 44 and 52 weeks Fasting serum glucose lipid and iron profile at 0 24 and 52 weeks Serum parathyroid hormone at 0 and 52 weeks Serum inflammatory markers at 0 12 24 36 and 52 weeks
Inflammatory markers include serum C-reactive protein CRP interleukin-6 IL-6 leptin adiponectin tumor necrosis factor alpha TNF-alpha and fibrinogen levels as suggested by other groups 35-38
Nutritional assessment
Nutritional status will assessed by subjective global assessment SGA comprehensive malnutrition-inflammation score MIS normalized protein nitrogen appearance NPNA serum albumin level anthropometric lean body mass LBM and fat-free edema-free body mass FEBM
SGA will be performed at -4 0 12 24 36 and 52 weeks by a single observer The 4-item 7-point scoring system proposed by Enia et al 39 will be used MIS will be performed at -4 0 12 24 36 and 52 weeks The calculation of MIS has been described previously 40 Briefly MIS consists of 4 main parts and 10 components all scored from 0 normal to 3 very severe The total score ranges from 0 to 30
FEBM and PNA will be measured by creatinine kinetics at 0 24 and 52 weeks A 24-hour dialysate and urine collections will be performed Total and peritoneal KtV are determined by standard methods Residual GFR is calculated as average of 24-hour urinary urea and creatinine clearance FEBM is calculated according to the formula of Forbes and Brunining 41 PNA is derived from the Randersons formula 42 It is further normalized to standard body weight
Anthropometric measurements will be performed at 0 12 24 36 and 52 weeks by a single observer This include bicep tricep subscapular and supra-iliac skin fold thickness and midarm muscle circumference Derived variables by anthropometric measurements including lean body mass LBM and percentage of body fat will be computed by standard formula 43
Pulse wave velocity
Pulse wave velocity PWV an index of aortic stiffness is measured using an automatic computerized recorder at 0 24 and 52 weeks The results will be analyzed by the Complior SP program Artech Medical France Briefly pressure-sensitive transducers are placed over the neck carotid artery wrist radial artery and groin femoral artery with the patient in the supine position on day of haemodialysis treatment before putting patient to the dialysis machine PWV of the carotid-femoral and carotid-radial territory is calculated by dividing the distance between the sensors by the time corresponding to the period separating the start of the rising phase of the carotid pulse wave and that of the femoral and also the radial pulse waves The procedure takes 10 to15 seconds to complete The test will be performed by the same observer to eliminate effect of intra-observer variation
Health-related quality of life
Patient acceptance and satisfaction will be assessed by the Chinese translation of Kidney Disease Quality of Life Short Form KDQOL-SFTM version 13 at 0 and 52 weeks
Outcome
The major outcome measure is nutritional status as detailed above The schedule of various tests is summarized in Appendix 2 Secondary outcomes include the followings
Change in arterial pulse wave velocity Total number of days of hospital admission during study period Composite cardiovascular end point cardiovascular death non-fatal myocardial infarction or stroke hospital admission for unstable angina coronary intervention transient ischemic attack or lower limb ischemia Number of episode of peritonitis during study period All cause mortality
Transplantation conversion to hemodialysis recovery of renal function and transfer out of the unit will also be recorded
4 Potential Outcomes
In Hong Kong 80 of end-stage renal failure patients are treated with peritoneal dialysis PD In 2004 there were over 3000 PD patients in Hong Kong Malnutrition cardiovascular disease and systemic inflammatory state are all common in our clinical practice They are major causes of patient morbidity and mortality The financial implication is considerable
As a readily available anti-cytokine therapy thalidomide may represent a valuable treatment of the MIA syndrome The proposed study will provide important insight on the clinical benefit of thalidomide treatment in malnourished PD patients which accounts for about one-third of our dialysis population
Data Analysis
Statistical analysis will be performed by SPSS for Windows software version 115 SPSS Inc Chicago IL All data will be expressed in mean - standard deviation unless otherwise specified Serial changes of nutritional parameters dialysis adequacy and inflammatory markers will be compared to the baseline values by analysis of variance for multiple measures MANOVA Serial change in residual GFR is examined by Wilcoxons rank sum test with Bonferronis correction for multiple comparison because of skewed data Nutritional status and systemic inflammatory markers after one year will be compared between the 2 groups by Students t-test for parametric data Hospitalization and peritonitis rate between the groups are compared by Kruskal-Wallis test because the data will be highly skewed Actuarial patient survival will be compared by logrank test with Kaplan-Meier survival curves and treatment group as stratifying variable
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