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A Long-Term, Open-Label Extension Study on the Safety of Treatment With Lanthanum Carbonate, a New Phosphate Binder, in Patients Receiving Hemodialysis

Posted on: Saturday, 11 June 2005, 03:00 CDT

Key words: End-stage renal disease - Hyperphosphatemia - Lanthanum carbonate - Long-term study

ABSTRACT

Background: Lanthanum carbonate, a new phosphate binder, is effective in reducing serum phosphorus levels in patients with end- stage renal disease. A 1-year extension study to two randomized controlled studies was conducted to evaluate the long-term safety of lanthanum carbonate in patients who received hemodialysis.

Research design and methods: Patients from two previous lanthanum carbonate studies were eligible to continue treatment in a 1-year open-label extension. A total of 77 patients (N = 77; 11 from Study 1, 66 from Study 2) were enrolled in this extension. The mean age of patients was 60.9 years (SD 12.5 years); 65% were male and 35% were female. All patients received lanthanum carbonate at the optimal dose for phosphorus control, determined in their previous study. Safety and tolerability were assessed by monitoring adverse events, laboratory parameters, and vital signs. The number of patients who maintained serum phosphorus levels at ≤ 5.9 mg/dL (1.9mmol/L) was recorded, along with serum calcium, calcium phosphorus product, and parathyroid hormone levels.

Results: Lanthanum carbonate was well tolerated and was associated with few treatment-related adverse events. The most commonly reported adverse events were nausea (26.0%), peripheral edema (23.4%), and myalgia (20.8%). No treatment-related serious adverse events occurred. By Week 4, the mean serum phosphorus level had decreased by approximately 1 mg/dL to 5.7 2.0 mg/dL (1.84 0.7 mmol/L). At the end of the study, the mean pre-dialysis serum phosphorus level was 5.7 1.4 mg/dL (1.84 0.5 mmol/L); 53% of patients had controlled phosphorus levels. Calcium phosphorus product decreased during Week 1 and remained within a clinically acceptable range thereafter. There were no clinically significant changes in serum calcium, or parathyroid hormone levels.

Conclusion: Lanthanum carbonate is well tolerated and is effective for the long-term maintenance of serum phosphorus control in patients with end-stage renal disease.

Introduction

Abnormalities in phosphorus balance, eventually leading to hyperphosphatemia, are almost inevitable in patients with chronic kidney disease (CKD). Increasing serum phosphorus levels disrupt the delicate balance between calcium, parathyroid hormone (PTH), and calcitriol, and directly stimulate PTH secretion from the parathyroid gland1-3. In addition, reduced levels of renal calcitriol synthesis that accompany renal failure, and an associated reduction in intestinal absorption of calcium, can result in hypocalcemia, a major stimulus for PTH secretion1. The resulting secondary hyperparathyroidism that develops as a consequence of uncontrolled hyperphosphatemia causes calcium to be released from the bones, giving rise to high-turnover bone disease, a form of renal osteodystrophy1,4,5.

Hyperphosphatemia is also an important determinant of vascular calcification, which is associated with serious cardiovascular complications and increased patient mortality6. In the absence of normal renal excretion and the presence of excess phosphorus, calcium accumulates within the cellular compartments. This leads to calcium precipitation and deposition in soft tissues and organs, including the heart and vascular system. The risk of increased mortality seems to be related to elevated calcium load and calcium phosphorus (Ca P) product6,7.

As uncontrolled hyperphosphatemia is associated with significantly increased morbidity and mortality7, it is essential that serum phosphorus is maintained within clinically acceptable limits in patients with CKD (recent guidelines issued by the National Kidney Foundation suggest that phosphorus levels should be maintained below 5.5mg/dL [1.8mmol/L])8. In end-stage renal disease (ESRD), this invariably results in the need for dietary phosphorus restriction and the use of phosphatebinder therapy.

Aluminum, given orally in the form of aluminum hydroxide, is a highly effective phosphate binder9. However, high levels, primarily absorbed from dialysis fluid, were found to be associated with dialysis-related encephalopathy syndrome10. Accumulation of aluminum was also found to affect bone-matrix mineralization and osteoblast activity, leading to the development of osteomalacia11. It is, therefore, no longer widely used in the management of hyperphosphatemia, but is an effective short-term rescue therapy when other treatments have failed12,13.

Calcium-based salts have replaced aluminum-based salts as the most widely used type of phosphate binders in patients with ESRD12. However, the combination of calcium-based binders with vitamin D analogs for the treatment of hyperparathyroidism14 may increase the internal absorption of calcium and phosphorus, and lead to over- suppression of PTH production. This could increase the risk of low- turnover bone disease and aggravate the risks associated with hypercalcemia and hyperphosphatemia.

Sevelamer hydrochloride is the first non-aluminum-, non-calcium- based phosphate binder available for the management of hyperphosphatemia15. Treatment with this synthetic ion-exchange polymer reduces serum phosphorus levels in patients with ESRD15,16 and has beneficial effects on markers of coronary artery and aortic calcification compared with calcium-based agents17. Other benefits include a reduction in total serum cholesterol, low-density lipoprotein cholesterol16 and PTH concentration17. However, the high doses required to achieve target phosphorus levels (6.5 2.9g/day, 8 800-mg tablets)17 may adversely affect treatment compliance. Concerns have also been raised over reduced bicarbonate levels during treatment18,19. Lanthanum carbonate (FOSRENOL*, Shire Pharmaceuticals Development, UK) is a new non-aluminum-based, non- calcium-based phosphate binder, which has been developed for the treatment of hyperphosphatemia in patients with ESRD on dialysis. Placebo- and comparator-controlled trials have shown that lanthanum carbonate effectively reduces serum phosphorus levels20-22. A study by Joy et al.20 reported that the incidence of adverse events in patients who received short-term treatment with lanthanum carbonate was similar to that reported in patients who received placebo. The most frequently reported events were gastrointestinal20,22. Treatment was not associated with hypercalcemia. In this study, we investigated the safety of lanthanum carbonate in a 1-year, open- label extension study to two previous trials. The efficacy of treatment in this patient group was also assessed.

Patients and methods

Study design

This was a 1-year, open-label extension study evaluating the long- term safety of lanthanum carbonate in hemodialysis patients who had received treatment in one of two previous trials (Study 1(21) and Study 2(20)). Study 1 was a dose-finding study incorporating a 1-3- week, single-blind, placebo-controlled run-in phase; a 6-week, double-blind phase during which subjects were randomized to receive fixed doses of lanthanum carbonate (225-2250 mg/day) or placebo; and a 2-week, single-blind, placebo-controlled run-out phase, followed by an extension period of up to 48 weeks21. Study 2 consisted of a 1- 3-week screening and washout period; a 6-week, open-label dose- titration period (lanthanum carbonate doses providing 750-3000mg/ day of elemental lanthanum, titrated weekly as necessary to maintain serum phosphorus control); and a 4-week, randomized, double-blind, placebo-controlled period20.

Patients entering the extension study, reported here, received the dose of lanthanum carbonate already established as optimal for serum phosphorus control in the previous study. The dose could be titrated during the study to maintain serum phosphorus levels at ≤ 5.9 mg/dL (1.9 mmol/L).

During the study, patients returned for weekly visits for the first 4 weeks and then at Weeks 6, 12, 20, 28, 36, 44, and 52. At Week 1, pre-dialysis vital signs, post-dialysis weight, and a complete medical history were recorded. A physical examination was also performed and information collected relating to concomitant medications. At each subsequent visit, pre-dialysis vital signs, post-dialysis weight, concomitant medications, and adverse events were recorded. A complete blood profile, including biochemical and hematological parameters, was carried out at entry to the study and at each visit from Week 4 onwards. In addition, pre-dialysis serum phosphorus levels (PSPLs) and calcium levels were evaluated at Weeks 2, 3, and 4. Plasma lanthanum levels were determined at Weeks 6, 20, 36, and 52, and electrocardiograms (ECGs) were recorded at Weeks 1, 6, 20, 36, and 52. All patients received dialysis three times per week. When blood was required for laboratory evaluations, or to assay plasma lanthanum levels, samples were drawn at the first visit of the week, prior to the start of the dialysis session.

The study protocol and consent form were approved by institutional review boards prior to study initiation. In addition, this study was performed in accordance with the International Conference on Harmonization guidelines on Good Clinical Practice. Each patient signed an informed consent form after receiving information on what the study invo\lved.

Study population

To be eligible for inclusion in the study, patients must have participated in either of the two previously described lanthanum carbonate trials. Patients were required to have a serum phosphorus level of between 2 and 10mg/dL (0.65 and 3.2 mmol/L). Patients from Study 2 with a serum phosphorus level ≥ 10 mg/dL (3.2 mmol/L) after randomization were also eligible to enter the study, as these patients may have been receiving placebo immediately before entry into the current extension study. Patients were excluded from the study if they had withdrawn from Study 2 prior to randomization, or because of adverse events that were considered possibly or definitely related to study medication. Women with a positive pregnancy test at screening or who were breast-feeding, or those of childbearing age who did not agree to use effective birth control methods were also excluded from the study.

Concomitant medications taken by patients were recorded throughout the study. Medications excluded from the time of screening until the end of the study included other phosphate binders, calcium-based compounds, and other investigational drugs or over-the-counter products containing aluminum, calcium, phosphates, or magnesium. In the event of serum calcium levels falling below normal levels during the study, oral calcium, as a supplement, was permitted at bedtime, without meals, i.e. outside the lanthanum carbonate dosing regimen.

Safety and efficacy variables

Adverse events were recorded at each visit throughout the study. Adverse events were rated according to severity, as mild, moderate, or severe; and according to whether they were unlikely, likely, or definitely related to lanthanum carbonate treatment. A serious adverse event (SAE) was defined as any adverse event that resulted in death, a life-threatening experience, hospitalization/prolonged hospitalization, persistent or significant disability, or a congenital anomaly/birth defect. Safety evaluations also included monitoring vital signs and lanthanum levels, laboratory evaluations, and ECG results.

To ensure that the doses of lanthanum carbonate administered maintained serum phosphorus control, efficacy assessments were scheduled at each visit throughout the study. The control of PSPLs, defined as maintaining serum phosphorus levels within the clinically acceptable limit of ≤ 5.9 mg/dL (1.9 mmol/L), was used to assess efficacy in this study. Patients were classified as responsive to lanthanum carbonate if their PSPLs were controlled at least 75% of the time. Other efficacy-related parameters were assessed, including the effects on serum calcium, Ca P product, and PTH levels.

Patients were removed from the study if the Ca P product level exceeded 80 mg^sup 2^/dL^sup 2^ (6.45 mmol^sup 2^/L^sup 2^) after Week 6; serum phosphorus level dropped below 2mg/dL (0.65mmol/L) or rose above 10mg/dL (3.2mmol/L) during the study; calcium level rose above 11 mg/dL (2.74mmol/L); or if the PTH level rose above 500 pg/ mL (53pmol/L) from baseline.

Analysis

No sample size estimation was done statistically for this study as only those patients who were randomized in Study 1 and Study 2 were allowed to participate. Plasma lanthanum concentrations were plotted and analyzed for changes from baseline using a one-sample t- test. Summary statistics are presented for serum phosphorus, calcium, Ca P product, and PTH levels.

Results

Patient disposition

A total of 77 patients (men and women, aged ≥ 18 years) were enrolled in the study; 11 (69% of patients) from Study 1, and 66 (80% of patients) from Study 2. These patients formed the intent- to-treat population, and their baseline demographics are summarized in Table 1. Forty-five patients (58.4%) withdrew from the study, the main reason being withdrawal of consent (15.6%; n = 12). Other reasons included exceeding safety criteria (7.8%; n = 6); protocol violation (6.5%; n = 5); patient received kidney transplant (6.5%; n = 5); death (2.6%; n = 2); adverse events (10.4%; n = 8); seven patients (9.1%) withdrew for other reasons. The remaining 32 patients completed the study. Average treatment compliance (calculated by the investigator on the basis of the return of medication at each visit) was 82.1%.

Safety evaluations

Exposure to lanthanum carbonate is summarized in Table 2. Mean total exposure to lanthanum carbonate (including exposure in the previous studies) was 232.6 128.9days. Four patients (5.2%) were treated for longer than 1 year and 37 patients (48.1%) were treated for longer than 9 months. Twenty patients (26%) had received treatment for 3 months or less.

Adverse events were reported in 72 patients (93.5%) treated with lanthanum carbonate. Adverse events occurring with an incidence ≥ 10% are summarized in Table 3. The most common body system categories of adverse events were gastrointestinal (55.8%), respiratory (55.8%), general disorders (49.4%), cardiovascular (36.4%), dialysis graft complications (36.4%), and musculoskeletal (36.4%). The most commonly reported adverse events were nausea (26.0%), peripheral edema (23.4%), and myalgia (20.8%).

Six patients (7.8%) experienced 12 incidents that were considered to be drug-related; all occurred in the gastrointestinal system and included constipation (2.6%), diarrhea (1.3%), dyspepsia (3.9%), glossitis (1.3), nausea (1.3%), and tooth disorder (1.3%). Only dyspepsia (frequency, 3.9%) and constipation (frequency, 2.6%) occurred in more than one patient.

Eight patients (10.4%) withdrew from the study due to adverse events, which included nausea; diarrhea; vomiting; myocardial infarction; elevated PTH; constipation; tongue irritation and inflammation; noncompliance; serum phosphorus level > 10mg/dL (3.2 mmol/L); elevated PTH level; and, in one case, long-term rehabilitation, which led the investigator to terminate the patient from the study. Two of these events, constipation and tongue irritation, were considered to be related to study treatment.

Table 1. Patient baseline demographics of the study population (N = 77)

Table 2. Exposure to lanthanum carbonate in patients (N = 77)

Thirty-seven patients (48.1%) experienced an SAE, the most frequently reported being dialysis graft complications (7.8% of patients), sepsis (6.5%), and hospitalization for a renal transplant (6.5%). The only other SAEs with an incidence > 5% were dialysis graft occlusion, osteomyelitis, and myocardial infarction (all 5.2%). None of these SAEs were unexpected and reflect the ESRD in the study population. No SAEs were considered to be treatment- related. Three patients died (3.9%) either during the study or within 30 days of the final dose; these deaths were due to cardiac arrest, uremia, or myocardial infarction, and none of the deaths were considered to be related to the study drug.

Pre-dialysis lanthanum levels were also assessed during the study (Table 4). The changes in plasma lanthanum levels from Week 6 at Weeks 20, 36, and 52 were not statistically significant. Relatively consistent levels of lanthanum were recorded throughout the study.

The percentage of patients in each treatment group that had normal values in laboratory tests at baseline and abnormal values after treatment is summarized in Table 5. At the final visit, ≥ 10% of patients had significant decreases in hemoglobin (16.9%), red blood cell (RBC) count (14.3%), bicarbonate (13.0%) and hematocrit (13.0%). Parameters that increased significantly in ≥ 10% of the patients were potassium (15.6%) and glucose (11.7%). The percentage of patients that experienced significant changes in their laboratory values during treatment was low. Biochemical and hematological parameters were typical for a population of ESRD patients. Changes observed in these parameters did not increase with time and were not considered to be clinically significant or related to study treatment. Analysis of ECG data revealed no clinically significant changes for morphology or for heart rate, including the PR, QRS, QT, or QTcB intervals.

Table 4. Plasma lanthanum levels ( SD) (intent-to-treat population) in the 1-year extension study to evaluate the long-term safety of lanthanum carbonate

Serum phosphorus levels

Mean PSPLs throughout the 1-year study are shown in Figure 1. At Week 1, mean PSPL was 6.6 2.0mg/dL (2.1 0.7 mmol/L). By Week 4, mean PSPL had decreased by approximately 1 mg/dL to 5.7 2.0 mg/dL (1.8 0.7 mmol/L), and at the end of the study PSPL was 5.7 1.4 mg/ dL (1.8 0.5 mmol/L). In addition, up to Week 20, the decrease from the baseline value reported at each visit was statistically significant. Sixty-six per cent of patients had PSPL controlled to the target level of ≤ 5.9 mg/dL (1.9 mmol/L) by Week 6. During the remainder of the study, more than 63% of patients had controlled PSPL values except at Week 20 (55%) and Week 52 (53%).

Table 3. Summary of adverse events occurring in ≥ 10% of patients (N = 77) in the long-term study of lanthanum carbonate

Table 5. Number (%) of patients with normal laboratory test values at baseline that were abnormal at the final visit in the 1- year extension study to evaluate the long-term safety of lanthanum carbonate in patients receiving hemodialysis

Figure 1. Mean serum phosphorus levels in the intent-to-treat population over time in the 1-year extension study to evaluate the long-term safety of lanthanum carbonate, p value is from one sample t-test in change from baseline: *p ≤ 0.05, **p ≤ 0.01, ***p ≤ 0.001. The numbers above the bars indicate the number of patients in the analysis at each time point in the study. (Note: to convert serum phosphorus in mg/dL to mmol/L, multiply by 0.3229)

Changes in serum calcium, Ca P product, and PTH level are shown in Figure 2. Mean calcium level increased slightly up to Week 44 (from Week-1 values of 8.8 mg/ dL [2.2 mmol/L] to 9.5 mg/dL [2.4 mmol/L]); as only four patient\s received bedtime calcium, it is unlikely that this led to the increase in levels. The increases from Week 1, however, remained constant after Week 20 (Figure 2). Although the increases at Weeks 20, 28, 36, and 44 were statistically significant (p = 0.0023-0.0391), none were considered to be clinically significant. Mean serum Ca P product level, which was closely related to serum phosphorus level, decreased at the start of treatment and remained within clinically acceptable levels (43-60 mg^sup 2^/dL^sup 2^ [3.2-4.8 mmol^sup 2^/L^sup 2^]) throughout the study. Median PTH levels did not show any substantial change throughout the study and remained within recommended levels for stage 5 chronic kidney disease (150-300 pg/mL [16.5-33.0 pmol/ L])8. None of the changes were statistically significant and none were considered to be clinically relevant.

Figure 2. Mean levels of calcium and Ca F product, and median PTH levels in the intent-to-treat population over time for the 1- year extension study to evaluate the long-term safety of lanthanum carbonate. The normal range of values for calcium and the clinically acceptable range for Ca P product are shown as shaded areas on the graphs. The dotted lines show the levels at the start of the extension. The numbers above the bars indicate the number of patients in the analysis at each time point in the study. (Note: to convert serum calcium in mg/dL to mmol/L, multiply by 0.2495; Ca P product in mg^sup 2^/dL^sup 2^ to mmol^sup 2^/L^sup 2^, divide by 12.4; and serum PTH in pg/mL to pmol/L, multiply by 0.106; Ca P = calcium phosphorus; PTH = parathyroid hormone; SD = standard deviation)

Discussion

In this open-label extension study, lanthanum carbonate, at doses providing 750-3000 mg/day of elemental lanthanum, was well tolerated during a treatment period of 1 year. Treatment effectively maintained serum phosphorus control throughout the study. Given the nature of ESRD and the long duration of this study, the incidence and nature of adverse events observed is as anticipated in this patient population. Drug-related adverse events were uncommon, being reported in only 7.8% of patients. All of these were gastrointestinal in nature and none were serious. SAEs occurred in 48.1% of patients; all were unrelated to lanthanum carbonate treatment. None of these SAEs were unexpected and reflect the ESRD in the study population; for example, hospitalization rates for congestive heart failure, ischemic heart disease and arrhythmia are generally two to seven times higher for ESRD versus non-ESRD patients23. Patients with ESRD are also more likely to be hospitalized for non-cardiovascular conditions, including pneumonia (two to four times higher incidence) and bacteremia/septicemia23. Eight patients (10.4%) were withdrawn because of adverse events. None of the reasons for withdrawal from the study were unexpected in this patient group. Overall, there was no evidence to suggest that the use of lanthanum carbonate in this population increased the risk of serious or severe adverse events, and the incidence of death (3.9%) was not any greater than would be expected (overall mortality rates in patients with ESRD in 2002 were 248 deaths per 1000 patient years)23. Additionally, plasma lanthanum levels remained constant throughout the study. Changes in laboratory values, vital signs, and ECG parameters were not clinically significant and were not considered to be related to lanthanum carbonate.

In this study, the clinically acceptable level of serum phosphorus control was pre-defined as ≤ 5.9 mg/dL (1.9 mmol/ L). At baseline, the mean PSPL was 6.6 2.0 mg/dL (2.1 0.7 mmol/ L). This is likely to be due to the inclusion of patients from Study 2 who may have received placebo prior to commencing this extension trial. However, after 4 weeks of lanthanum treatment, the mean PSPL value had fallen to 5.7 mg/dL (1 .84 mmol/L), and remained at < 5.9 mg/dL (1.9 mmol/L) for the rest of the treatment period, except for Week 20, when the value was 6.0 mg/dL (1.94 mmol/L). Thus, lanthanum carbonate was able to effectively maintain serum phosphorus control over the 52-week study period.

The ability to reduce and maintain PSPL is supported by the proportion of 'phosphorus-controlled' (≤ 5.9 mg/dL [1.9 mmol/ L]) patients over the duration of treatment. By the sixth week of lanthanum treatment, 66% of the patients were controlled. During the remainder of the study, more than 63% of patients had controlled PSPL values, except at Week 20 (55%) and Week 52 (53%). The reasons for the decrease in the proportion of patients with controlled PSPL at Week 20 and Week 52 are not apparent.

At the time this study was designed, the clinically acceptable limit for serum phosphorus was generally regarded to be ≤ 5.9 mg/dL (1.9 mmol/L). It is now recognized that lowering this limit to ≤ 5.5 mg/dL (1.8 mmol/L) has significant benefits for patients8. The importance of maintaining the serum phosphorus level at or below 5.5 mg/dL (1.8 mmol/L) is based on the observation that in hemodialysis patients, there is a progressive relationship between the degree of hyperphosphatemia and increasing cardiovascular calcification. Studies have shown that serum phosphorus levels ≥ 5.5 mg/dL (1.8 mmol/L) are capable of up- regulating osteopontin in vascular smooth muscle cells and in this way may contribute to accelerated vascular calcification in patients with ESRD14. After 52 weeks of lanthanum carbonate treatment in this study, 43% of patients achieved PSPL ≤ 5.5 mg/dL (1.8 mmol/ L), despite the fact that investigators were not actively titrating patients to this lower limit.

Serum calcium, Ca P product, and PTH levels remained stable throughout the study. The majority of patients (72.7%) were also receiving concomitant vitamin D therapy. Patients, therefore, were able to receive therapeutic agents to adequately control both serum phosphorus and serum PTH, without causing an increase in serum calcium levels. This is not always achievable with calcium-based phosphate binders, as concomitant administration of vitamin D may increase the risk of hypercalcemia24,25.

Lanthanum carbonate treatment is well tolerated for maintaining long-term serum phosphorus control in patients with ESRD undergoing hemodialysis. Lanthanum carbonate was able to maintain efficacy in controlling serum phosphorus over 1 year without increasing the risk of SAEs, or affecting serum calcium, Ca P product, and PTH levels.

Acknowledgments

This research was supported by Shire Pharmaceutical Development.

* FOSRENOL is a registered trade name of Shire Pharmaceuticals Development, UK

References

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15. Chertow GM, Dillon MA, Amin N, Burke SK. Sevelamer with and without calcium and vitamin D: observations from a long-term open- label clinical trial. J Ren Nutr 2000;10:125-32

16. Chertow GM, Burke SK, Lazarus JM, et al. Poly [allylamine hydrochloride] (RenaGel): a noncalcemic phosphate binder for the treatment of hyperphosphatemia in chronic renal failure. Am J Kidney Dis 1997;29:66-71

17. Chertow GM, Burke SK, Raggi P. Sevelamer attenuates the progression of coronary and aortic calcification in hemodialysis patients. Kidney Int 2002;62:245-52

18. Genzyme. Renagel package insert. 2004

19. Gallieni M, Cozzolino M, Brancaccio D. Transient decrease of serum bicarbonate levels with sevelamer hydrochloride as the phosphate binder. Kidney Int 2000;57:1776-7

20. Joy MS, Finn WF. Randomized, double-blind, placebo- controlled, dose-titration, Phase III study assessing the efficacy and tolerability of lanthanum carbonate: a new phosphate binder for the treatment of hyperphosphatemia. Am J Kidney Dis 2003;42:96\-107

21. Finn WF, Joy MS, Hladik GA, and the Lanthanum Study Group. Efficacy and safety of lanthanum carbonate for reduction of serum phosphorus in patients with chronic renal failure receiving hemodialysis. Clin Nephrol 2004;62:193-201

22. Hutchison AJ, Speake M, Al Baaj F. Reducing high phosphate levels in patients with chronic renal failure undergoing dialysis: a 4-week, dose-finding, open-label study with lanthanum carbonate. Nephrol Dial Transplant 2004;19:1902-6

23. US Renal Data System (USRDS). Annual data report, 2003

24. Locatelli F, Cannata-Andia JB, Drueke TB, et al. Management of disturbances of calcium and phosphate metabolism in chronic renal insufficiency, with emphasis on the control of hyperphosphataemia. Nephrol Dial Transplant 2002;17:723-31

25. Delmez JA, Tindira CA, Windus DW, et al. Calcium acetate as a phosphorus binder in hemodialysis patients. J Am Soc Nephrol 1992;3:96-102

William F. Finn and Melanie S. Joy on Behalf of the LAM-308 Study Group

Department of Medicine, University of North Carolina, Chapel Hill, NC, USA

Address for correspondence: Dr Melanie S. Joy, Department of Medicine, Division of Nephrology and Hypertension, University of North Carolina, CB 7155, 348 MacNider Building, Chapel Hill, NC 27599-7155, USA. Tel.: +1 919 966 2561; Fax: +1 919 966 4251; email: Melanie_Joy@med.unc.edu

Copyright Librapharm May 2005

Source: Current Medical Research and Opinion

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