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Arterial Stiffness and Calcifications in Haemodialysis Patients on Sevelamer or Calcium Acetate

Primary Purpose

Haemodialyzed Patients, Hyperphosphatemia

Status
Withdrawn
Phase
Not Applicable
Locations
Romania
Study Type
Interventional
Intervention
Calcium acetate
Sevelamer
Sponsored by
Romanian Society of Nephrology
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Haemodialyzed Patients focused on measuring haemodialysis, hyperphosphatemia, sevelamer, calcium acetate

Eligibility Criteria

18 Years - 60 Years (Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria: more than 3 months on haemodialysis willingness to participate age 18-60 yrs pre-dialysis blood pressure 120-160 mmHg in the last month prior to the initiation of study or recent (<1 Mo) addition of a new antihypertensive drug iPTH at entry 200-800 pg/mL (as per severe hyperparathyroidism) serum calcium at entry 2.2-2.6 mmol/L Exclusion Criteria: haemodynamic instability uncontrolled hypertension any severe, debilitating disease associated with a reduced survival any major cardiovascular event in the last 12 month before study cinacalcet therapy before study entrance history of parathyroidectomy documented history of poor compliance serious gastrointestinal disease

Sites / Locations

  • "Dr Carol Davila" Teaching Hospital of Nephrology
  • "CI Parhon" Clinical Hospital

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Experimental

Arm Label

I

II

Arm Description

Calcium acetate 670 mg tablets

label sevelamer (RenagelR) 800 mg tablets

Outcomes

Primary Outcome Measures

changes in arterial stiffness parameters
changes in calcification score

Secondary Outcome Measures

composite of all-cause mortality, cardiovascular mortality and major cardiovascular events

Full Information

First Posted
August 10, 2006
Last Updated
December 21, 2017
Sponsor
Romanian Society of Nephrology
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1. Study Identification

Unique Protocol Identification Number
NCT00364000
Brief Title
Arterial Stiffness and Calcifications in Haemodialysis Patients on Sevelamer or Calcium Acetate
Official Title
Arterial Stiffness and Arterial Calcifications Evolution in ESRD Haemodialysis Patients Treated by Sevelamer or Calcium Acetate
Study Type
Interventional

2. Study Status

Record Verification Date
December 2017
Overall Recruitment Status
Withdrawn
Why Stopped
Limitted financial resources
Study Start Date
January 2012 (Actual)
Primary Completion Date
July 2015 (Actual)
Study Completion Date
December 2017 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Romanian Society of Nephrology

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

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 arterial/coronary 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 (N=15) 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 arterial/coronary 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-aged)haemodialysis 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 (>1.8 mmol/l) 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 1:1 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 1-1.6 mmol/L and a serum calcium level <2.6 mmol/L. The maximum elemental calcium dose/day in the calcium acetate arm will not exceed 1.5 g. Serum ionized calcium will be adjusted for the serum albumin concentration using the formula: adjusted Ca = total measured calcium +0.8 x (4.0-albumin g/dL). 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 centers/Universities The K/DOQI 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 pg/ml; vitamin D not at all if serum calcium >2.6 mmol/L Analysis will include: correlation between PWV, AIx, calcification scores and Ca-P metabolism parameters, lipid parameters etc capability of reaching the N/KDOQI 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 14.56 m/s to 13.34 m/s i.e. a decrease of approximatively 9% from pre-Sevelamer values. If normalized to BP (PWV divided by corresponding BP level) than PWV/BP decreased from 10.2 m/s/mmHg to 9.3 m/s/mmHg - i.e. 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 7.19+/-1.88 m/s, or if corrected for corresponding BP values: PWV/BP = 5.14 +/- 1.3 m/s/mmHg. AIx is typically 27.9±11.9% 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 (i.e. no increase in PWV - "conservative approach", but different from Takenaka's results where an increase in PWV was reported - see above), the standard deviation of the PWV is 1.88 m/s in our experience or 1.3 m/s/mmHg, 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 PWV/BP is used), 216 total. This will also have sufficient power detect a decrease in AIx of only 4.6% or 16.5% 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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Haemodialyzed Patients, Hyperphosphatemia
Keywords
haemodialysis, hyperphosphatemia, sevelamer, calcium acetate

7. Study Design

Primary Purpose
Treatment
Study Phase
Not Applicable
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
0 (Actual)

8. Arms, Groups, and Interventions

Arm Title
I
Arm Type
Active Comparator
Arm Description
Calcium acetate 670 mg tablets
Arm Title
II
Arm Type
Experimental
Arm Description
label sevelamer (RenagelR) 800 mg tablets
Intervention Type
Drug
Intervention Name(s)
Calcium acetate
Intervention Description
Calcium acetate in 240 chronic HD patients
Intervention Type
Drug
Intervention Name(s)
Sevelamer
Intervention Description
label sevelamer (RenagelR) 800 mg tablets
Primary Outcome Measure Information:
Title
changes in arterial stiffness parameters
Time Frame
6 months
Title
changes in calcification score
Time Frame
6 months
Secondary Outcome Measure Information:
Title
composite of all-cause mortality, cardiovascular mortality and major cardiovascular events
Time Frame
1 year

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
60 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: more than 3 months on haemodialysis willingness to participate age 18-60 yrs pre-dialysis blood pressure 120-160 mmHg in the last month prior to the initiation of study or recent (<1 Mo) addition of a new antihypertensive drug iPTH at entry 200-800 pg/mL (as per severe hyperparathyroidism) serum calcium at entry 2.2-2.6 mmol/L Exclusion Criteria: haemodynamic instability uncontrolled hypertension any severe, debilitating disease associated with a reduced survival any major cardiovascular event in the last 12 month before study cinacalcet therapy before study entrance history of parathyroidectomy documented history of poor compliance serious gastrointestinal disease
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Adrian Covic, Prof
Organizational Affiliation
"CI Parhon" Clinical Hospital, Iasi
Official's Role
Study Director
First Name & Middle Initial & Last Name & Degree
Gabriel Mircescu, Prof
Organizational Affiliation
"Dr Carol Davila" Teaching Hospital of Nephrology, Bucharest, Romania
Official's Role
Study Director
Facility Information:
Facility Name
"Dr Carol Davila" Teaching Hospital of Nephrology
City
Bucharest
ZIP/Postal Code
010731
Country
Romania
Facility Name
"CI Parhon" Clinical Hospital
City
Iasi
Country
Romania

12. IPD Sharing Statement

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Arterial Stiffness and Calcifications in Haemodialysis Patients on Sevelamer or Calcium Acetate

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