Ignite Creation Date:
2024-05-05 @ 4:59 PM
Last Modification Date:
2024-10-26 @ 9:26 AM
Study NCT ID:
NCT00364000
Status:
WITHDRAWN
Last Update Posted:
2017-12-22
First Post:
2006-08-10
Brief Title:
Arterial Stiffness and Calcifications in Haemodialysis Patients on Sevelamer or Calcium Acetate
Sponsor:
Romanian Society of Nephrology
Organization:
Romanian Society of Nephrology
Study Overview
Official Title:
Arterial Stiffness and Arterial Calcifications Evolution in ESRD Haemodialysis Patients Treated by Sevelamer or Calcium Acetate
Status:
WITHDRAWN
Status Verified Date:
2017-12
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Limitted financial resources
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
End-stage renal disease ESRD is a state of increased arterial stiffness of extensive vessel calcifications compared with the non-renal population Both arterial stiffness and arterial calcifications are potent predictors of all-cause and cardiovascular mortality in ESRD patients Several studies have documented the direct relationship between the extent and severity of arterialcoronary calcifications and outcome in dialysis patients The relationship is strong no matter if arterial calcifications were quantified by electron-beam computed tomography or a radiological calcification score Calcifications are early and progressive events in these patients PWV is strongly related to the degree of sonographic determined arterial calcifications and EBCT-derived coronary artery calcium score in chronic kidney disease patients
Calcium-based phosphate binders are associated with progressive coronary artery and aortic calcification especially when mineral metabolism is not well controlled
According to recent studies sevelamer hydrochloride is a potent non-calcium-containing phosphate binder well tolerated in ESRD Compared with calcium-based phosphate binders sevelamer is less likely to cause hypercalcemia low levels of PTH and progressive coronary and aortic calcification in hemodialysis patients Moreover sevelamer has a favorable effect on the lipid profile
Less is known about the relationship between sevelamer treatment and progression of arterial stiffness To date there is one single study examining the influence of sevelamer versus calcium carbonate on the evolution of arterial stiffness in a very small number N15 of haemodialysis patients These study used the same patients as historical controls thus being methodologically rather weak Moreover the follow-up was quite short - 6 month
The aim of the trial is to to quantify in a randomized opened-labeled controlled trial the effect of sevelamer hydrochloride on the evolution of arterial stiffness parameters pulse wave velocity and the augmentation index in chronic haemodialysis patients and to correlate these parameters with arterial calcification assessed by a previous described radiological score of arterial calcification and echocardiographic parameters left ventricular hypertrophy LV dilatation systolic and diastolic dysfunction
Calcium-based phosphate binders are associated with progressive coronary artery and aortic calcification especially when mineral metabolism is not well controlled
According to recent studies sevelamer hydrochloride is a potent non-calcium-containing phosphate binder well tolerated in ESRD Compared with calcium-based phosphate binders sevelamer is less likely to cause hypercalcemia low levels of PTH and progressive coronary and aortic calcification in hemodialysis patients Moreover sevelamer has a favorable effect on the lipid profile
Less is known about the relationship between sevelamer treatment and progression of arterial stiffness To date there is one single study examining the influence of sevelamer versus calcium carbonate on the evolution of arterial stiffness in a very small number N15 of haemodialysis patients These study used the same patients as historical controls thus being methodologically rather weak Moreover the follow-up was quite short - 6 month
The aim of the trial is to to quantify in a randomized opened-labeled controlled trial the effect of sevelamer hydrochloride on the evolution of arterial stiffness parameters pulse wave velocity and the augmentation index in chronic haemodialysis patients and to correlate these parameters with arterial calcification assessed by a previous described radiological score of arterial calcification and echocardiographic parameters left ventricular hypertrophy LV dilatation systolic and diastolic dysfunction
Detailed Description:
End-stage renal disease ESRD is a state of increased arterial stiffness of extensive vessel calcifications compared with the non-renal population Both arterial stiffness and arterial calcifications are potent predictors of all-cause and cardiovascular mortality in ESRD patients Underlying mechanisms for increased stiffness in uremia are not well-defined but may include chronic fluid overload arterial calcifications microinflammation increased sympathetic hyperactivity activation of the renin-angiotensin system increased lipid oxidation and abnormalities of the nitric oxide system
Several studies have documented the direct relationship between the extent and severity of arterialcoronary calcifications and outcome in dialysis patients The relationship is strong no matter if arterial calcifications were quantified by electron-beam computed tomography or a radiological calcification score Calcifications are early and progressive events in these patients PWV is strongly related to the degree of sonographic determined arterial calcifications and EBCT-derived coronary artery calcium score in chronic kidney disease patients
Calcium-based phosphate binders are associated with progressive coronary artery and aortic calcification especially when mineral metabolism is not well controlled
Sevelamer hydrochloride is a potent non-calcium-containing phosphate binder well tolerated in ESRD Compared with calcium-based phosphate binders sevelamer is less likely to cause hypercalcemia low levels of PTH and progressive coronary and aortic calcification in hemodialysis patients Moreover sevelamer has a favorable effect on the lipid profile
Less is known about the relationship between sevelamer treatment and progression of arterial stiffness To date there is one single study examining the influence of sevelamer versus calcium carbonate on the evolution of arterial stiffness in 15 HD patients These study used the same patients as historical controls thus being methodologically rather weak Moreover the follow-up was quite short - 6 month
The aim of the study is to quantify in a randomized opened-labeled controlled trial the effect of sevelamer hydrochloride on the evolution of arterial stiffness parameters pulse wave velocity and the augmentation index in chronic haemodialysis patients and to correlate these parameters with arterial calcification assessed by a previous described radiological score of arterial calcification and echocardiographic parameters left ventricular hypertrophy LV dilatation systolic and diastolic dysfunction 240 chronic clinical stable young-to-medium-agedhaemodialysis patients will be included Follow-up 12 month After screening the patients will enter a washout period for all currently used phosphate binders for 2 weeks All patients with hyperphosphatemia 18 mmoll during the wash-out period eligible for randomization into the treatment phase
Stratification will consider the Framingham calcification score age gender diabetes HD vintage The patient will be randomized computer-generated in a 11 ratio to open label sevelamer RenagelR 800 mg tablets or calcium acetate 670 mg tablets Because of the size appearance and taste of the tablets neither the subjects nor the investigators will be blinded
Adherence to treatment will be assessed by regular bill count The starting dose of sevelamer and calcium acetate determined by replacing the phosphate binder used by the patient prior to the washout period on a gram to gram basis The dose of phosphate binder should be titrated to achieve a serum phosphorus level in the target range of 1-16 mmolL and a serum calcium level 26 mmolL The maximum elemental calcium doseday in the calcium acetate arm will not exceed 15 g
Serum ionized calcium will be adjusted for the serum albumin concentration using the formula adjusted Ca total measured calcium 08 x 40-albumin gdL After 4 weeks the dose of phosphate binder vitamin D analogue and the dialysate calcium concentration can be titrated to reach the target range
Study conduction will be conducted strictly in compliance with the Declaration of Helsinki and Committees on Human Research in the participating centersUniversities The KDOQI targets for serum phosphate serum-calcium and PTH are aimed during the study
Data on intact parathormone serum-calcium and phosphate Ca-P product will be collected monthly in the first three month every 3 month later on
Vitamin D allowance only if during the study PTH raise 500 pgml vitamin D not at all if serum calcium 26 mmolL
Analysis will include
correlation between PWV AIx calcification scores and Ca-P metabolism parameters lipid parameters etc
capability of reaching the NKDOQI guidelines regarding control of secondary hyperparathyroidism - sevelamer hydrochloride versus calcium acetate
stratification of PWV and AIx dynamics according to different categories The only published reference in the literature is by Takenaka et al NDT 2005 they showed in a small study that after 6 months of sevelamer treatment PWV decreases from 1456 ms to 1334 ms ie a decrease of approximatively 9 from pre-Sevelamer values If normalized to BP PWV divided by corresponding BP level than PWVBP decreased from 102 msmmHg to 93 msmmHg - ie again a decrease of approximatively 9 from pre-Sevelamer values
Of note in the previous 6 months while on CaCO3 PWV increased significantly by 30 to 40 from baseline study values study of Takenaka has a cross-over design 6-months on CaCO3 followed by 6-months on Sevelamer Also there is no information provided on AIx There is no information in the literature on the impact of Sevelamer on EID GTN- vascular function or on EDD flow-dependent hyperemia or beta2 agonist stimulation-vascular function
In our experience the mean PWV is 719-188 ms or if corrected for corresponding BP values PWVBP 514 - 13 msmmHg AIx is typically 279119 in HD patients
If we assume that the Sevelamer group treatment group will have the same 9 decrease in PWV at 6 months from baseline the Ca-binder group control group will have no change ie no increase in PWV - conservative approach but different from Takenakas results where an increase in PWV was reported - see above the standard deviation of the PWV is 188 ms in our experience or 13 msmmHg the ratio of 1 between the control and thre treatment arms than for a power of 80 and a confidence interval of 95 we need 108 patients in each arm 105 if PWVBP is used 216 total This will also have sufficient power detect a decrease in AIx of only 46 or 165 from baseline in the treatment arm This is usually less than that recorded after different acute interventions GTN salbutamol dialysis session or after transplantation in HD patients
Compliance is good in our units and transplantation is rare Therefore we expect only a dropout rate of 10 Thus the final study population should be 240 patients 120 patients should receive Sevelamer for 6 months
Several studies have documented the direct relationship between the extent and severity of arterialcoronary calcifications and outcome in dialysis patients The relationship is strong no matter if arterial calcifications were quantified by electron-beam computed tomography or a radiological calcification score Calcifications are early and progressive events in these patients PWV is strongly related to the degree of sonographic determined arterial calcifications and EBCT-derived coronary artery calcium score in chronic kidney disease patients
Calcium-based phosphate binders are associated with progressive coronary artery and aortic calcification especially when mineral metabolism is not well controlled
Sevelamer hydrochloride is a potent non-calcium-containing phosphate binder well tolerated in ESRD Compared with calcium-based phosphate binders sevelamer is less likely to cause hypercalcemia low levels of PTH and progressive coronary and aortic calcification in hemodialysis patients Moreover sevelamer has a favorable effect on the lipid profile
Less is known about the relationship between sevelamer treatment and progression of arterial stiffness To date there is one single study examining the influence of sevelamer versus calcium carbonate on the evolution of arterial stiffness in 15 HD patients These study used the same patients as historical controls thus being methodologically rather weak Moreover the follow-up was quite short - 6 month
The aim of the study is to quantify in a randomized opened-labeled controlled trial the effect of sevelamer hydrochloride on the evolution of arterial stiffness parameters pulse wave velocity and the augmentation index in chronic haemodialysis patients and to correlate these parameters with arterial calcification assessed by a previous described radiological score of arterial calcification and echocardiographic parameters left ventricular hypertrophy LV dilatation systolic and diastolic dysfunction 240 chronic clinical stable young-to-medium-agedhaemodialysis patients will be included Follow-up 12 month After screening the patients will enter a washout period for all currently used phosphate binders for 2 weeks All patients with hyperphosphatemia 18 mmoll during the wash-out period eligible for randomization into the treatment phase
Stratification will consider the Framingham calcification score age gender diabetes HD vintage The patient will be randomized computer-generated in a 11 ratio to open label sevelamer RenagelR 800 mg tablets or calcium acetate 670 mg tablets Because of the size appearance and taste of the tablets neither the subjects nor the investigators will be blinded
Adherence to treatment will be assessed by regular bill count The starting dose of sevelamer and calcium acetate determined by replacing the phosphate binder used by the patient prior to the washout period on a gram to gram basis The dose of phosphate binder should be titrated to achieve a serum phosphorus level in the target range of 1-16 mmolL and a serum calcium level 26 mmolL The maximum elemental calcium doseday in the calcium acetate arm will not exceed 15 g
Serum ionized calcium will be adjusted for the serum albumin concentration using the formula adjusted Ca total measured calcium 08 x 40-albumin gdL After 4 weeks the dose of phosphate binder vitamin D analogue and the dialysate calcium concentration can be titrated to reach the target range
Study conduction will be conducted strictly in compliance with the Declaration of Helsinki and Committees on Human Research in the participating centersUniversities The KDOQI targets for serum phosphate serum-calcium and PTH are aimed during the study
Data on intact parathormone serum-calcium and phosphate Ca-P product will be collected monthly in the first three month every 3 month later on
Vitamin D allowance only if during the study PTH raise 500 pgml vitamin D not at all if serum calcium 26 mmolL
Analysis will include
correlation between PWV AIx calcification scores and Ca-P metabolism parameters lipid parameters etc
capability of reaching the NKDOQI guidelines regarding control of secondary hyperparathyroidism - sevelamer hydrochloride versus calcium acetate
stratification of PWV and AIx dynamics according to different categories The only published reference in the literature is by Takenaka et al NDT 2005 they showed in a small study that after 6 months of sevelamer treatment PWV decreases from 1456 ms to 1334 ms ie a decrease of approximatively 9 from pre-Sevelamer values If normalized to BP PWV divided by corresponding BP level than PWVBP decreased from 102 msmmHg to 93 msmmHg - ie again a decrease of approximatively 9 from pre-Sevelamer values
Of note in the previous 6 months while on CaCO3 PWV increased significantly by 30 to 40 from baseline study values study of Takenaka has a cross-over design 6-months on CaCO3 followed by 6-months on Sevelamer Also there is no information provided on AIx There is no information in the literature on the impact of Sevelamer on EID GTN- vascular function or on EDD flow-dependent hyperemia or beta2 agonist stimulation-vascular function
In our experience the mean PWV is 719-188 ms or if corrected for corresponding BP values PWVBP 514 - 13 msmmHg AIx is typically 279119 in HD patients
If we assume that the Sevelamer group treatment group will have the same 9 decrease in PWV at 6 months from baseline the Ca-binder group control group will have no change ie no increase in PWV - conservative approach but different from Takenakas results where an increase in PWV was reported - see above the standard deviation of the PWV is 188 ms in our experience or 13 msmmHg the ratio of 1 between the control and thre treatment arms than for a power of 80 and a confidence interval of 95 we need 108 patients in each arm 105 if PWVBP is used 216 total This will also have sufficient power detect a decrease in AIx of only 46 or 165 from baseline in the treatment arm This is usually less than that recorded after different acute interventions GTN salbutamol dialysis session or after transplantation in HD patients
Compliance is good in our units and transplantation is rare Therefore we expect only a dropout rate of 10 Thus the final study population should be 240 patients 120 patients should receive Sevelamer for 6 months
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