Manchester Institute of Nephrology and Transplantation, Manchester Royal Infirmary, UK
Correspondence and offprint requests to: Dr Alastair J. Hutchison, Manchester Royal Infirmary, Oxford Road, Manchester M13 9WL, UK. Email: alastair.hutchison{at}cmmc.nhs.uk
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Abstract |
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Methods. This was a double-blind, placebo-controlled, parallel-group study consisting of three phases: a 2 week washout period; a 4 week, open-label, dose-titration phase; and a 4 week, double-blind, placebo-controlled phase. After washout, patients (n = 59) received lanthanum (375 mg/day), titrated up to a maintenance dose (maximum: 2250 mg) that achieved control of serum phosphate levels between 1.3 and 1.8 mmol/l (4.035.58 mg/dl). After titration, patients were randomized to receive their maintenance dose of lanthanum (n = 17) or placebo (n = 19) for 4 weeks. Control of serum phosphate was the primary efficacy assessment. Levels of calcium, parathyroid hormone, calcium x phosphate product and lanthanum as well as adverse events were evaluated.
Results. By the end of titration, 70% of patients had serum phosphate levels 1.8 mmol/l. Lanthanum carbonate continued to control serum phosphate levels in the double-blind phase. At the end of the study, 64.7% of lanthanum carbonate-treated patients were controlled compared with 21.4% in the placebo group. Results in patients receiving CAPD were similar to those seen in the group as a whole. Mean parathyroid hormone levels (P = 0.41) and calcium x phosphate product (P<0.001) were both higher in the placebo than the lanthanum carbonate group.
Conclusions. Lanthanum carbonate is an effective phosphate binder able to control serum phosphate and calcium x phosphate product.
Keywords: dialysis; end-stage renal disease; hyperphosphataemia; lanthanum carbonate; phosphate; phosphorus
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Introduction |
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Hyperphosphataemia has been treated using aluminium- and calcium-based salts. However, there have been a number of safety concerns associated with the use of these conventional phosphate-binding agents. Aluminium is a highly effective phosphate binder but has well-documented toxic effects, such as osteomalacia and encephalopathy. These adverse effects severely restrict its use [46]. Although calcium-based drugs do not have such toxicity, it is often necessary to use high doses; as a result, large numbers of pills are required. Importantly, these drugs contribute to an increased level of calcium x phosphate product and have been implicated in the development of metastatic calcification and, potentially, cardiovascular disease [7,8].
Consequently, there has been much research into the development of alternatives to aluminium- and calcium-based agents. Sevelamer hydrochloride is a useful new treatment option for haemodialysis patients, which is not associated with the safety concerns described above. However, it does have some drawbacks, including generation of mild acidosis with reduced bicarbonate levels and its high pill burden to achieve adequate phosphate control, making patient compliance a potential problem [912].
Lanthanum carbonate (Fosrenol®; Shire Pharmaceuticals Group, Basingstoke, Hampshire, UK) is a potent new, non-aluminium, non-calcium phosphate binder that has shown good efficacy compared with other agents in pre-clinical and human studies [1315]. Lanthanum is a naturally occurring rare-earth element with a molecular weight of 139 Da that was discovered by Mosander in 1839. Environmental exposure occurs via diet and drinking water and lanthanum has been found in human bone in a control dialysis population at levels 1 µg/g [16]. Lanthanum is very poorly absorbed from the intestine, with an absolute oral bioavailability in man of 0.00089% [17]. This limits systemic tissue deposition and biopsy studies in dialysis patients have shown bone concentrations of
5.5 µg/g after 1 year and
9 µg/g after 4 years [17]. No bone toxicity attributable to lanthanum was evident in a 1 year bone biopsy study in dialysis patients, comparing lanthanum carbonate and calcium carbonate [16]. Animal studies have shown lanthanum carbonate to have similar phosphate-binding efficacy to aluminium, with no evidence of aluminium-related toxicity [13,14]. Recently reported pre-clinical and clinical data suggest that lanthanum carbonate is an effective phosphate binder with very low toxicity, minimal systemic absorption and a good safety profile [1519].
To investigate the potential of lanthanum carbonate further, we undertook a double-blind, placebo-controlled, dose-finding study in patients receiving haemodialysis or continuous ambulatory peritoneal dialysis (CAPD). Data from the initial open-label titration phase have been reported previously [19] and are included here, briefly, for completeness.
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Subjects and methods |
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Exclusion criteria included patients with hypercalcaemia, severe hyperparathyroidism [parathyroid hormone (PTH) levels >500 ng/l], serum phosphate >3.0 mmol/l (9.3 mg/dl) after the washout phase, other clinically significant abnormal laboratory values, a positive pregnancy test, significant gastrointestinal disorder (including known active peptic ulcer, Crohn's disease, ulcerative colitis, irritable bowel syndrome and past or present malignancies), unstable dietary habits, life-threatening malignancy or HIV-positive status. Patients with a history of drug or alcohol abuse and those who, in the opinion of the investigators, would not comply with treatment requirements were also not eligible to enter the study.
Patients were withdrawn if phosphate levels were not controlled and exceeded 3.0 mmol/l or if it were felt that it would be detrimental for the patient to continue the study. The trial was conducted in accordance with the principles of Good Clinical Practice and the Declaration of Helsinki and its subsequent revisions. Written informed consent was given.
Study design
This was a multi-centre, double-blind, placebo-controlled, parallel-group, dose-finding study consisting of three phases: a 2 week washout period; a 4 week, open-label, dose-titration phase; and a 4 week, double-blind, placebo-controlled phase.
After screening, patients who met the inclusion criteria underwent a 2 week washout of their previous phosphate binders. Serum phosphate levels were monitored at the end of each week. Patients whose serum phosphate had risen to >1.8 mmol/l (5.58 mg/dl) were eligible to enter the open-label, dose-titration phase with lanthanum carbonate, while those patients whose serum phosphate levels remained 1.8 mmol/l were withdrawn. To ensure that changes in serum phosphate levels occurring during the study were due to the study medication and not a result of significant changes in dietary phosphate intake, patients' diets were monitored with diet sheets and diary cards. Vitamin D could be continued at an unchanged dose, but not initiated, during the study.
At the end of washout/start of titration (visit 1), a blood sample was taken for biochemical evaluation, including phosphate and lanthanum levels. A 24 h urine sample was collected and an aliquot was sent to the hospital laboratory service for determination of creatinine clearance. Throughout the study, patients returned for weekly visits and any change in their status was assessed. Standard practice for haemodialysis patients in the investigational centres was to take blood samples before dialysis and after the longest interdialytic period.
Patients' lanthanum doses were titrated on a weekly basis, according to their serum phosphate levels, from a daily dose of 375 mg up to a maximum of 2250 mg lanthanum. All patients received lanthanum as chewable tablets (containing 125 or 250 mg lanthanum) taken in three equally divided doses with meals.
At the end of the titration phase (visit 5), patients with serum phosphate levels between 1.3 and 1.8 mmol/l (4.035.58 mg/dl) entered the double-blind, parallel-group phase. Patients were randomized in a 1:1 ratio to receive either their lanthanum maintenance dose or placebo for 4 weeks (visits 59). There was no washout between the titration and double-blind phase.
Efficacy assessments
The primary efficacy endpoint was reduction of serum phosphate levels to between 1.3 and 1.8 mmol/l at the end of double-blind treatment (visit 9). Secondary efficacy parameters included changes over time in pre-dialysis serum calcium and PTH levels, adverse events (coded according to the World Health Organization Adverse Reaction Terminology version 98.3) and pre-dialysis vital signs and laboratory tests, assessed at weekly visits.
Patients' diets were monitored with diary cards issued at visit 0 (screening), visit 4 and visit 8. Details of meals were recorded for 3 consecutive days and their completed diary cards returned at the next visit.
Serum lanthanum levels were assessed every 2 weeks. Lanthanum was assayed by the Analytical Services Group at AEA Technology plc (Harwell International Business Centre, Didcot, Oxfordshire, UK) using a validated inductively coupled plasmamass spectrometer assay. The limit of quantification was 0.5 ng/g.
Statistical analysis
Groups were compared with respect to continuous data using analysis of variance, t-tests or Wilcoxon rank sum tests as appropriate. Frequency distributions were tested using Chi-squared or Fisher's exact tests. Final titrated dose was compared between groups using Wilcoxon rank sum test. Groups were compared with respect to phosphate, calcium, PTH and calcium x phosphate product using analysis of covariance, with visit 5 level (end of titration) as a covariate. Data relating to safety and tolerability, such as laboratory measures and vital signs, were tabulated and listed.
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Results |
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A total of 14 patients who completed the titration phase did not enter the placebo-controlled phase. Five of these patients were recruited in a pilot group to establish that the specified doses of lanthanum were consistent with acceptable safety and efficacy profiles. These patients were included in the titration-phase analysis only [19] and took no further part in the study. Three patients were withdrawn because of protocol violations, one because of non-compliance and five because of uncontrolled phosphate levels. Therefore, 36 patients entered the double-blind phase. Of these patients, 34 completed the study. Two patients withdrew from the double-blind phase after randomization: one for a protocol violation and one for an adverse event (both within the placebo group).
The majority of patients were titrated up from a lanthanum dose of 375 mg/day, with only one requiring downward titration to 250 mg/day. Twenty-two patients were titrated to a dose of 1500 mg/day and 11 reached 2250 mg/day (mean dose: 1278 mg/day).
Efficacy
Dose-titration phase
The data for this part of the study have been presented previously [19]. By the end of the titration phase (visit 5), 60% of patients (n = 30/50) had controlled phosphate levels (1.31.8 mmol/l) and 70% (n = 35/50) had serum phosphate levels 1.8 mmol/l.
Double-blind, placebo-controlled phase
Patients in the double-blind phase were well balanced in terms of the final lanthanum dose at the end of the titration phase (Table 2). Two patients who entered the double-blind phase failed to complete the study both were in the placebo group.
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Mean PTH levels at the start of the placebo-controlled phase (visit 5) were similar in the two treatment groups (Figure 3A). Thereafter, mean levels were higher in those patients receiving placebo than in those receiving lanthanum carbonate. There was, however, no significant difference in PTH levels between the lanthanum carbonate group (216±179 ng/l) and placebo group (250±226 ng/l) at visit 9 (P = 0.41). Calcium x phosphate product levels decreased during the titration phase and thereafter remained similar in the lanthanum carbonate group and increased in the placebo group. From visit 6 onwards, the mean calcium x phosphate product was higher for those patients treated with placebo than for those maintained on lanthanum carbonate (Figure 4). The mean calcium x phosphate product was significantly lower in lanthanum carbonate-treated patients [3.62±0.75 mmol2/l2 (44.9±9.3 mg2/dl2)] than in placebo-treated patients [4.71±0.87 mmol2/l2 (58.4±10.8 mg2/dl2)] at visit 9 (P<0.001), predominantly due to increasing serum phosphate levels in the placebo group.
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Compliance, as measured weekly by pill counts, was at least 94% for patients treated with lanthanum carbonate and 93% for those treated with placebo during the double-blind phase. There were no marked differences in compliance at any visit.
Safety
The occurrence of adverse events was similar in both the lanthanum carbonate and placebo groups (Table 3). During dose titration, 86% (n = 51/59) of patients experienced at least one adverse event. These were believed to be treatment-related in 44% (n = 26/59) of patients. Of the CAPD patients, 87% (n = 34/39) experienced adverse events; the proportion with treatment-related events (62%; n = 24/39) was higher in this group.
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The most common adverse events and treatment-related events throughout the study were gastrointestinal in nature [experienced by 56% (n = 33/59) and 37% (n = 22/59) of patients, respectively]. Nausea (19%; n = 11/59) and vomiting (17%; n = 10/59) were the most common individual adverse events. During the double-blind phase, four gastrointestinal adverse events occurred in three patients in the lanthanum carbonate group compared with seven such adverse events in four patients in the placebo group.
Seven patients experienced serious adverse events, none of which were thought by the investigators to be related to the study treatment. During the study, eight patients withdrew primarily because of adverse events. Three lanthanum carbonate-treated patients had nausea (with vomiting and hypotension in one case); retrosternal discomfort, pruritus, shoulder pain and menorrhagia were specified as the reason for withdrawal of one patient treated with lanthanum carbonate each; and one patient receiving placebo had pruritus. There were no deaths during the study.
Lanthanum concentration
Serum lanthanum levels were low in all patients. At visit 4, 22 of 46 patients (48%) had serum lanthanum levels below the limit of quantification (0.5 ng/g). Levels above the limit of quantification for 24 of 46 individual patients ranged from 0.51 to 4.1 ng/g. Mean and median levels (with values <0.5 ng/g set to 0) were 0.50 and 0.51 ng/g, respectively.
At the end of the study, nine of 16 lanthanum carbonate-treated patients and four of 16 patients receiving placebo had detectable levels of lanthanum. Mean lanthanum levels were 0.67±0.98 ng/g in the lanthanum carbonate-treated group and 0.14± 0.26 ng/g in the placebo group. The detectable levels in the group receiving lanthanum carbonate at the end of the study ranged from 0.61 to 3.90 ng/g and in the placebo group from 0.51 to 0.71 ng/g. The patient who recorded the highest level of lanthanum at the end of the study experienced no adverse events.
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Discussion |
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The primary endpoint of the study was the proportion of patients for whom per-protocol-defined control of phosphate levels was achieved rather than a specific decrease in phosphate relative to placebo. At the end of the study, serum phosphate levels were controlled in 65% (n = 11/17) of lanthanum carbonate-treated patients and 21% (n = 3/14) of placebo-treated patients. Patients who switched from lanthanum carbonate to placebo after the dose-titration phase showed a rapid increase in phosphate levels within 1 week of stopping lanthanum carbonate and by study end, phosphate levels were similar to those at the end of washout. Notably, results in patients receiving CAPD were similar to those seen in the group as a whole.
The significant increase in phosphate levels following 4 weeks of placebo treatment, compared with lanthanum-treated patients, resulted in higher calcium x phosphate product and a trend to higher PTH levels in placebo-treated patients at the end of the study. As lanthanum carbonate reduced phosphate levels without increasing calcium levels, calcium x phosphate levels remained within normal values.
The metabolism of phosphate, calcium and PTH are interlinked and, with the growing recognition that derangements in mineral and bone metabolism in patients with chronic kidney disease (CKD) are associated with increased morbidity and mortality, effective management must be applied early in the course of CKD.
Lanthanum carbonate is a specific phosphate binder that in pre-clinical studies has been shown to bind phosphate with potency similar to that of aluminium and with no pH dependence within a clinically relevant pH range [15,20]. Our study shows that lanthanum carbonate is an effective phosphate binder that can control serum phosphate levels in patients with ESRD receiving haemodialysis or CAPD. This supports results from a placebo-controlled trial of lanthanum carbonate by Joy and Finn [18]. In this study, lanthanum carbonate was associated with significantly lower serum phosphate, calcium x phosphate product and PTH levels compared with placebo.
For the vast majority of patients in our study, the starting dose of 375 mg/day was too low to control phosphate levels and it appears that the majority (65%) require a dose of 7502250 mg for adequate control. Higher doses would appear to be required for
30% of patients, especially if one were to aim for the lower Kidney Disease Outcomes Quality Initiative target for serum phosphate of <1.49 mmol/l [21], introduced after the start of this study. Studies have shown that doses of
3750 mg/day are well tolerated in patients with ESRD [16,18].
Adverse events occurred at a rate expected in this population. The use of lanthanum carbonate in patients undergoing CAPD or haemodialysis, however, was generally well tolerated. As with other phosphate binders, the most common adverse events were gastrointestinal in nature and, in a minority of cases, nausea (with or without vomiting) led to treatment withdrawal. The adverse event profile for lanthanum carbonate was not markedly different from placebo in those patients who had already received titrated lanthanum carbonate for 4 weeks. There were no treatment-related serious adverse events.
Pre-clinical and early clinical data suggest that lanthanum absorption is minimal [15] and the low plasma levels of lanthanum in our study support this evidence. Furthermore, in animals, it has been shown that lanthanides undergo predominantly biliary, rather than renal, excretion [22]. These properties limit the systemic deposition of lanthanum and the potential for adverse effects [16,17]. Moreover, no bone toxicity attributable to lanthanum was evident in a 1 year bone-biopsy study comparing lanthanum carbonate and calcium carbonate in dialysis patients. Lanthanum carbonate was also reported to be well tolerated in an additional Phase III study in patients with ESRD [18] and in the titration phase of the current study [19].
One possible limitation of the present study is a potential selection bias in the exclusion criteria, as investigators were permitted to exclude patients who were considered unlikely to comply with the study protocol. However, as the study was randomized and double-blinded, the investigators would not have known which patients would receive lanthanum carbonate or placebo. Removal of patients whom it was believed would not comply with the study regimen may, therefore, have reduced any potential bias in the comparison of lanthanum carbonate with placebo. Patients could also be withdrawn from the study if it was felt that continuing would have been detrimental. It is possible that this led to premature withdrawal of patients in the placebo group, whose phosphate levels increased during the study. However, as only two patients withdrew from the double-blind phase one for a protocol violation and one for an adverse event it seems unlikely that this had a substantial effect on the outcomes of the study.
In conclusion, lanthanum carbonate is an effective phosphate binder that may lead to better control of serum phosphate and calcium x phosphate product levels and may improve compliance owing to its convenient chewable, palatable formulation.
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References |
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