Members of the Lanthanum Carbonate Research Group: Takehiko Sakai, Masashi Iwasaki, Kazutake Nagakura, Koichi Murakami (Mihama Hospital); Takashi Kono (Mihama Narita Clinic); Ken Ando (Mihama Shizu Clinic); Yasuo Kimura, Junichi Sato (New Kashiwa Clinic); Yoshinari Tsuruta, Takaaki Obayashi, Kana Kanashiro (Meiyo Clinic); Hachiro Seno, Yasumitsu Mori, Hiroshi Murai, Naoyuki Nakao (Ama Kyoritsu Clinic); Masafumi Taki, Katsuhiko Arimoto, Tatsuya Matsubara (Shigei Medical Research Hospital); Misaki Moriishi, Hideki Kawanishi, Hiroshi Watanabe (Nakajima Tsutiya Clinic); Jun Minakuchi, Takuma Kato, Ikuro Hayashi, Akihito Kaibara, Kazuhiko Kawahara, Hayato Nishida, Hiroko Suzuki (Kawashima Hospital); Isao Takeda, Kazunori Kuwahara, Osamu Sugita (Kochi Rehabilitation Hospital); Susumu Miyake, Tomonaga Noguchi (Shimazu Hospital); Kenji Yuasa, Kazumichi Ota, Naotami Terao, Yasukazu Sen, Yoshie Iwasa (Kochi Takasu Hospital); Mari Ishida, Yuji Ishida, Shoko Nakao, Takeshi Kobayashi, Setsuko Yachiku, Chikashi Komura, Naoyuki Yao (Kitasaito Hospital); Yoshihiro Tsujimoto, Tsutomu Tabata, Hideki Tahara (Inoue Hospital); and Takeshi Nishiuchi, Takehiko Kimura (Kawashima Cardiovascular Clinic).
One Year Efficacy and Safety of Lanthanum Carbonate for Hyperphosphatemia in Japanese Chronic Kidney Disease Patients Undergoing Hemodialysis
Article first published online: 15 JUN 2009
© 2009 The Authors. Journal compilation © 2009 International Society for Apheresis
Therapeutic Apheresis and Dialysis
Volume 14, Issue 1, pages 12–19, February 2010
How to Cite
Shigematsu, T. and Lanthanum Carbonate Research Group (2010), One Year Efficacy and Safety of Lanthanum Carbonate for Hyperphosphatemia in Japanese Chronic Kidney Disease Patients Undergoing Hemodialysis. Therapeutic Apheresis and Dialysis, 14: 12–19. doi: 10.1111/j.1744-9987.2009.00697.x
- Issue published online: 12 FEB 2010
- Article first published online: 15 JUN 2009
- Received July 2008; revised February 2009.
- Calcium phosphate product;
- Lanthanum carbonate;
- Phosphate binder;
- Vitamin D
Lanthanum carbonate is a non-calcium-based phosphate binder for hyperphosphatemia in patients with chronic kidney disease (CKD). The efficacy and safety of lanthanum carbonate (LaC) on hyperphosphatemia in patients has been well documented in clinical trials in Western countries and recent relatively short-term clinical trials in Japan. Evidence supporting its safety and efficacy in Japanese patients for longer-term treatment is now desired for clinical practice. A non-controlled, open-label, multicenter, one year study of LaC to assess safety and its effect on the levels of serum phosphate, serum calcium and parathyroid hormone was performed with Japanese dialysis patients. Lanthanum carbonate was administered to patients at variable doses for a period of 46–52 weeks. Evaluation of the safety and efficacy of LaC in reducing serum phosphate was performed, in addition to extensive and systematic monitoring of the laboratory parameters related to bone turnover and cardiac health. A significant reduction in the serum phosphate level was demonstrated throughout the treatment period (P < 0.05), without any increase in the frequency or severity of drug-related adverse events such as vomiting, nausea, and stomach discomfort. There was no clinically relevant change in vital signs, or electrocardiograms for a period. The profiles for parathyroid hormone, bone alkaline phosphates, and osteocalcin were stable in the patients concomitantly treated with vitamin D. This study provides further evidence that the administration of LaC over a period of one year is safe and effective for the reduction of serum phosphate levels in CKD patients undergoing hemodialysis.
Hyperphosphatemia is a common complication of renal failure in patients with chronic kidney disease (CKD) and affects the majority of dialysis patients, contributing to the risk of secondary hyperparathyroidism, soft tissue calcification, parathyroid hyperplasia, failure to respond to vitamin D therapy, bone disorders, and death (1–3). Treatment of hyperphosphatemia has been a crucial component in the management of renal disease to decrease mortality and prevent these conditions. As one of the treatments for this disease, control of dietary phosphate intake is partially effective in reducing serum phosphate; however, this is challenging because of poor compliance and the difficulty in maintaining adequate protein, nutrient, and amino acid intake in patients (4). Phosphate binders are required in the majority of CKD patients to trap dietary phosphate and reduce its absorption.
Lanthanum carbonate (LaC) is a new non-aluminum- and non-calcium-containing phosphate binder that has recently become available for the management of hyperphosphatemia in patients on dialysis (approved by the Food and Drug Administration in 2004). Oral administration effectively decreases phosphate absorption from the gastrointestinal tract by the formation and excretion of highly insoluble complexes with the phosphate in foods (5). While it has been approved for clinical use in the USA and Europe, it was still under clinical development in Japan as at the end of 2008.
Data concerning the safety and efficacy of LaC in reducing serum phosphate levels are now accumulating in foreign clinical study reports. There are several relatively short-term clinical trials (6–11) and long-term clinical trials (12–17), which detail the safety and efficacy of LaC. However, there are few reports of concomitant administration of LaC and vitamin D therapy. In Japan, a randomized, placebo-controlled Phase II study(18) and a Phase III double-blind comparative study for determination of the optimum dose (19) both demonstrated the safety and efficacy of LaC in patients with CKD, but both were short-term trials. Therefore, it was thought to be useful to further investigate the drug's efficacy and safety in a one year study with extensive observation of laboratory parameters.
PATIENTS AND METHODS
This was a non-controlled, open-label, multicenter study lasting one year that assessed the following: the efficacy of LaC in reducing serum phosphate, and its safety in chronic kidney disease (CKD) patients with hyperphosphatemia undergoing maintenance hemodialysis. The study population included a group of patients coming from the previous Phase II dose response study (18) and another group of newly recruited patients. Analysis was performed for the total population consisting of the following three groups: (i) patients who had received the placebo in the Phase II study, and who were extended to this study (subjects from the placebo group); (ii) patients who had received LaC in the Phase II study, and who were extended to this study (subjects from the active group); and (iii) patients who were newly recruited in this study (newly recruited subjects) (Fig. 1).
The inclusion criteria for newly recruited subjects were the same as those in the previous Phase II dose response study(18); that is: (i) male or female outpatients, aged between 20 and 75 years; (ii) serum inorganic phosphate (Pi) before hemodialysis (HD) treatment ≥5.6 mg/dL, and < 10.0 mg/dL two weeks after the initiation of the washout period (Week −1); (iii) having undergone hemodialysis three times per week for CKD for at least three months; and (iv) with a stable dosage of vitamin D therapy for at least the previous month before the initiation of the washout period, if undergoing the therapy. Patients who came under any of the following exclusion criteria were excluded from the study: (i) serum Pi before HD ≥10.0 mg/dL during the washout period; (ii) corrected serum calcium level < 8.0 mg/dL or ≥11.0 mg/dL during the washout period; and (iii) serum intact parathyroid hormone (iPTH) ≥1000 pg/mL during the washout period.
For the newly recruited patients, the prior anti-hyperphosphatemic agents in the candidate patients were stopped and they then observed a three-week washout period. During the washout period they were to undergo designated observations and examinations to determine whether they met the inclusion criteria. The test drugs were initiated at the first meal after the end of the washout period and administered three times a day without water or with just a little water by chewing immediately after each meal. The patients in this study received 750 mg/day as the initial dose. The dose was increased or decreased by a unit of 750 mg/day, depending on serum Pi (target levels: ≥3.5 mg/dL and ≤5.5 mg/dL) and incidence of adverse events. The dose was changed on a weekly basis if required up to a maximum dose of 4500 mg/day. The total treatment period in this group was 52 weeks.
For the patients from the placebo and active groups from the Phase II study, the test drugs were initiated at the end of the double-blind treatment period of the dose response study. During the double-blind period of six weeks, a placebo or LaC at a dose of 750–3000 mg/day was administered to the patients(18). Irrespective of the doses allocated during this period, the patients received 750 mg/day as the initial dose. The LaC doses and any dose changes for these groups during the open-label treatment phase were exactly the same as those in the newly recruited group. Thus, the total treatment period was 46 weeks for the placebo group and 52 weeks for patients in the active group. In order to avoid confusion with the results interpretation, the data were summarized by adjusting the start of the open-label treatment when all patients took 750 mg/day to be Week 0.
Efficacy and safety analysis
The efficacy assessments were scheduled for each visit throughout the study to ensure that the serum Pi was within the target level (≥3.5 mg/dL and ≤5.5 mg/dL). The achievement rate of target serum Pi and serum-corrected calcium levels were also measured at each visit. Other efficacy-related parameters were assessed, including the changes in the serum calcium × phosphate product and serum iPTH levels. For the safety analysis, incidence of treatment-emergent drug-related adverse events, concomitant therapy, and treatment compliance were evaluated at each visit. Safety evaluations also included monitoring the vital signs, laboratory variables, electrocardiogram (ECG) parameters, and serum lanthanum levels.
Drug concentration measurement
The plasma lanthanum levels were measured by inductively coupled plasma mass spectrometry (ICP-MS). Blood samples for the measurement were collected before hemodialysis. Lithium heparinized vacuum tubes were used to take 6 mL of blood at each designated time point. The blood samples collected were centrifuged at 3000 rpm at 4°C for 10 min, and the plasma obtained was kept frozen until used for analysis.
Patients valid for the per-protocol (PP) analysis were the primary efficacy population for this study. All variables were analyzed descriptively with appropriate statistical methods: categorical variables by frequency tables and continuous variables by mean, standard deviation (SD), minimum, median, quartiles and maximum.
A total of 145 patients at 15 different centers were enrolled and all were included in the safety analysis for the study. The safety analysis included 27 patients from the placebo group, 107 patients from the active group, and 11 patients from the newly recruited group. Of these, 143 patients were included in the PP analysis. Two patients (one from the placebo group, and another from the Phase II LaC group) were excluded from the efficacy analysis because the active treatment periods for these patients were less than 14 days.
For patients valid for the PP analysis, the age ranged from 32 to 75 years (mean ± SD: 57.5 ± 9.8), height from 135.0 to 180.0 cm (160.8 ± 8.4), weight from 31.8 to 84.5 kg (58.9 ± 10.4), and duration on hemodialysis from 1.8 to 26.5 years (9.2 ± 5.7). Approximately 60% of the patients valid for the PP analysis were men. The distributions of these demographic factors were generally comparable between the treatment groups. The most common primary cause of renal failure in all treatment groups was chronic glomerulonephritis (51%), followed by diabetic nephropathy (19%). The baseline values for serum Pi (8.03 ± 1.51 mg/dL), corrected serum calcium level (9.33 ± 0.58 mg/dL), and serum calcium × phosphate level (74.2 ± 15.26 mg2/dL2) were similar across the three treatment groups. The majority of patients had received prior medication for hyperphosphatemia, most commonly a calcium-containing phosphate absorber, used in 82% of the patients, followed by sevelamer treatment (37%).
Dose of LaC during open-label treatment
Figure 2 shows the change in dose of LaC during the one year open-label treatment. Independent weekly dose adjustment based on the serum Pi value resulted in an increase in the lanthanum dose (average ± SD) from 750 ± 0 mg/day at Week 0 to 2098 ± 1151 mg/day at the end of treatment. The dose increases reached a plateau at Week 7, and it was similar in both the vitamin D therapy (+) and (−) sub-groups (data not shown). The doses of LaC at the end of treatment in these sub-groups were 2309 ± 1160 mg/day and 1650 ± 1012 mg/day, respectively.
One of the primary efficacy variables was the decrease in serum Pi from the baseline to the end of the one year LaC treatment period. Figure 3A shows the means and standard deviations of serum Pi over time from the start of open-label treatment. The mean serum Pi decreased from 8.03 ± 1.51 mg/dL at the baseline (Week 0) to 5.33 ± 1.33 mg/dL at Week 10 and the decreased Pi level was maintained afterward (5.33 ± 1.27 mg/dL at one year). The mean reductions in serum Pi from the baseline to each time point were within the range of −1.51 ± 1.48 mg/dL (Week 1, 95% CI: −1.76, −1.27) to −2.98 ± 2.00 mg/dL (Week 32, 95% CI: −3.36, −2.59), and at all time points the reductions were significant (P < 0.05).
Figure 4 shows the time-dependent change in the proportion of the patients who achieved the therapeutic serum Pi target of 3.5–5.5 mg/dL. The target achievement rate at Week 1 was 33.8%, but it increased gradually and reached 67.2% at Week 16, and was maintained at 56.4–70.1% thereafter. According to the therapeutic target set by the Japanese Society of Dialysis Therapy (JSDT guideline) of 3.5–6.0 mg/dL, the target achievement rates at those time points were 44.4, 78.1 and 69.8–81.7%, respectively. When we count the accumulated percentage of patients who achieved the target serum Pi of 3.5–5.5 mg/dL, 93% of patients reached the therapeutic target at least once by Week 20, and 96% by Week 40. Based on the JSDT guideline target range, 97% of patients reached the target at least once by Week 20, and 98% by Week 24.
In Figure 3, the time-course changes in the calcium × phosphate product (Fig. 3B), corrected serum calcium levels (Fig. 3C), and serum iPTH levels (Fig. 3D) are shown, respectively. The mean corrected serum calcium level was generally stable and ranged around 9.5 mg/dL throughout the treatment period. The mean serum calcium × phosphate product decreased from 74.20 ± 15.26 mg2/dL2 at baseline to 49.88 ± 11.93 mg2/dL2 at Week 10 and was maintained at this level thereafter (50.06 ± 12.08 mg2/dL2 at one year) (Fig. 3B). The mean reductions in the calcium × phosphate product from the baseline to each time point were within the range of −14.01 ± 13.47 mg/dL (Week 1, 95% CI: −16.25, −11.78) to −26.66 ± 19.31 mg/dL (Week 32, 95% CI: −30.37, −22.96), and at all time points the reductions were significant (P < 0.05). The serum iPTH level was generally stable throughout the treatment period with a median value of 262.0 pg/mL at baseline to 332.0 pg/mL at one year, but a slight increase was observed in later periods of the study (Fig. 3D).
Almost all patients (99%) experienced at least one adverse event during the study, and 57% had adverse events related to the study drug. Thirty-two patients (22%) experienced at least one serious adverse event and four patients (3%) had serious drug-related adverse events. Thirty-six patients (25%) were discontinued from the study because of adverse events. One death (acute myocardial infarction: assessed as unrelated to the study drug) was reported in this study. Most of the adverse events were mild or moderate in intensity. One subject (1%) had a drug-related adverse event (unstable angina) classified as severe. Table 1 summarizes the incidence of drug-related adverse events reported in at least 3% of patients. The most common (≥10%) drug-related adverse events were vomiting (31%), nausea (30%) and stomach discomfort (12%), which were all rated as mild in intensity. There were no clinically relevant changes in the mean laboratory parameters, vital signs, or ECG parameters. Table 2 shows that a tendency to increase was observed in the bone turnover parameters; that is, alkaline phosphatase (ALP), osteocalcin, type I collagen cross-linked N telopeptide (NTx), and bone-specific alkaline phosphatase (BAP).
|Adverse event||No. of patients (N = 145)|
|Any event||83 (57%)|
|Blood and lymphatic system disorders|
|Iron deficiency anemia||8 (6%)|
|Secondary hyperparathyroidism||8 (6%)|
|Stomach discomfort||18 (12%)|
|Upper abdominal pain||12 (8%)|
|Reflux esophagitis||6 (4%)|
|Abdominal distension||5 (3%)|
|Baseline||End of one year of treatment|
|ALP (U/L)||239.1 ± 97.6||318.9 ± 146.1|
|Osteocalcin (mg/L)||86.5 ± 70.4||124.5 ± 86.6|
|BAP (U/L)||24.2 ± 11.5||39.1 ± 23.6|
|NTx (nmol BCE/L)||168.8 ± 111.4||224.3 ± 141.1|
The mean plasma lanthanum levels in the present one year study slightly increased from 0.154 ng/mL in Week 2 to 0.164 ng/mL in Week 6, and then to 0.389 ng/mL at 7 months and 0.387 ng/mL at 1 year.
Effects of vitamin D usage
The overall distribution of patients who were administered oral vitamin D, injected with vitamin D, or who were not administered vitamin D were 68 (47.6%), 28 (19.6%), and 47 (32.9%) at the baseline, and 69 (48.3%), 40 (28.0%), and 34 (23.8%) at the last observation, respectively. The dose of vitamin D, either orally or by injection, was 1.42 ± 2.21 µg at the baseline, and 1.89 ± 2.63 µg at the last observation. The dose of LaC at the last observation was higher in vitamin D users (2237 ± 1186 mg/day, N = 113) than non-users (1600 ± 999 mg/day, N = 30). Changes from the baseline to the last observation in serum Pi, calcium × phosphate product, corrected serum calcium and iPTH were similar in the subgroups, as shown in Table 3.
|Change from baseline to the last observation||Vitamin D use|
|No (N = 30)||Yes (N = 113)|
|Serum inorganic phosphate†||−2.32 ± 1.76||−2.49 ± 2.28|
|Calcium × phosphate product†||−20.91 ± 15.15||−22.67 ± 20.46|
|Corrected serum calcium†||0.17 ± 0.58||0.09 ± 0.37|
|Serum intact parathyroid hormone‡||31 (−22, 85)||36 (−54, 14)|
The control of serum phosphate levels continues to be a challenging goal for practitioners treating patients with CKD. Hyperphosphatemia significantly increases the risk of morbidity and mortality in this population (1). Phosphate binders are generally required in the majority of CKD patients to reduce its absorption, but their efficacy may be dependent on the dosage used or the study population. The population in this study is considered to be representative of CKD patients undergoing maintenance hemodialysis in Japan. The most frequent primary diseases were chronic glomerulonephritis (43.6%) and diabetic nephropathy (31.4%), which contrasts greatly to those in the clinical trials conducted by Finn et al. (16) with a primary diagnosis distribution of diabetes (34–35%), hypertension (21–31%), and glomerulonephritis (12–14%). In Japan, 75% of hemodialysis patients were treated with calcium carbonate, and 26% with sevelamer for the control of hyperphosphatemia at the end of 2004, according to a survey by the Japanese Society for Dialysis Therapy (an overview of regular dialysis treatment in Japan as of 31 December 2004 (20).
Calcium carbonate has been widely used in Japan for the treatment of CKD; however, a high calcium load, especially >3000 mg/day (as stated in the JDST guideline), is believed to result in hypercalcemia. In addition, there is increasing evidence that a high intake of calcium binders is associated with PTH over-suppression, adynamic bone disease, soft tissue, and cardiovascular calcification (21–24). Therefore, the treatment for hyperphosphatemia should ideally have several targets: to control phosphate effectively and safely within the target levels without an excessive calcium load and hypercalcemia; and to control PTH levels by the use of active vitamin D. Previously published studies of sevelamer have documented the absence of the suppressive effect of sevelamer on PTH and an increased ability to prescribe vitamin D due to the relative lack of hypercalcemia (25), although sevelamer is not an ideal phosphate binder due to its side effect profile in the Japanese population(26). Thus, the current management strategies in Japan for hyperphosphatemia are limited by clinical trade-offs and have not adequately addressed the complexities of CKD. From this perspective, LaC seems to have a beneficial effect of avoiding over-suppression of PTH secretion and adynamic bone disease because it is a non-calcium phosphate binder.
We have shown in the present one year study that the treatment of CKD patients with LaC was very effective and safe in the reduction of serum Pi, without any incidence of hypercalcemia, although around 80% (N = 113/143) of patients had concomitant therapy with vitamin D. In fact, the corrected serum calcium level was maintained throughout the study period regardless of vitamin D therapy (Fig. 3C and Table 3). The reduction in serum Pi from the baseline to the end of the treatment was −2.61 ± 2.12 mg/dL (95% CI: −3.05, −2.17) (Fig. 3A). This is consistent with the value observed in the previous short-term (eight weeks long) Phase III double-blind study (−2.58 mg/dL), indicating that there is no difference in the effect of LaC on the reduction of serum Pi between short-term (eight weeks) and long-term (one year) treatment (19). The efficacy of LaC in controlling serum phosphate levels within the therapeutic target was also confirmed by the finding that 96% of patients reached the therapeutic target of 3.5–5.5 mg/dL at least once by Week 40, and 98% of patients reached the JSDT guideline target of 3.5–6.0 mg/dL at least once by Week 24. Regardless of the target range definition, more than half of the patients were within the target range after Week 16 (Fig. 4).
The decreases in the serum calcium × phosphate product were very similar to those of serum Pi (Fig. 3A,B), which is explained by the relatively constant calcium levels during the treatment period (Fig. 3C). The corrected serum calcium and PTH levels were relatively constant throughout the study period (Fig. 3C,D). These results were consistent with the results of previous long-term studies in Western countries (13–17) and a previous Japanese Phase III study (19).
The difference between the previous double-blind, short-term study(19) and the present one year study is the use of the comparator, calcium carbonate, and concomitant therapy with vitamin D. Because of the limitation in the number of patients with CKD in Japan, the present one year study has not adopted the comparator group, but instead evaluated the efficacy and safety of LaC, as well as the detailed laboratory values, vital signs, and ECG parameters for a period of one year with concomitant vitamin D therapy. Although there are limitations to the interpretation of results because this study was not a randomized controlled study comparing vitamin D administration, our data does provide the basic information that vitamin D and LaC can be safely co-administered to dialysis patients. Although vitamin D is known to increase calcium absorption from the gastrointestinal tract, changes in corrected serum calcium level were similar between vitamin D users and non-users (Table 3), suggesting little concern about hypercalcemia with concomitant vitamin D therapy. Considering the effects of calcium load and vitamin D dose on serum calcium level, LaC would be the best treatment option to treat hyperphosphatemia patients with hypercalcemia who require vitamin D therapy.
The common drug-related adverse events were mild vomiting, nausea, and stomach discomfort (Table 1), and the mean dose after the plateau was approximately 2000 mg/day (Fig. 2). Although it is difficult to make a precise comparison, the drug-related adverse events observed in this study seem similar to those experienced at the doses of 2250 and 3000 gm/day in the previous Phase II dose response study(18), indicating the stable safety of LaC in one year of treatment. There were no clinically relevant changes in vital signs or ECG parameters. In addition, we have extensively monitored the parameters related to bone turnover, such as osteocalcin, BAP and NTx (Table 2). There were no clinically relevant changes found in the mean bone turnover parameters except for the increase in ALP, but it was accompanied with increases in the other bone turnover parameters. This might be due to an increase in serum iPTH in later periods of the study. (Fig. 3D). This provides further evidence that LaC has a beneficial effect on bone, which was reported by Freemont et al. using bone histomorphometry (14). From the overall results, there was no indication of adynamic bone or cardiac malfunction in the study patients. Thus, LaC is considered to be effective, not only in reducing high phosphate levels, but also in avoiding hypercalcemia, and there may be further options regarding concomitant vitamin D therapy for secondary hyperthyroidism, although this patient group was not included in the present study or not observed during the one-year treatment period.
Plasma lanthanum levels at Week 6 in the previous dose response study were between 0.194 ng/mL and 0.349 ng/mL with different doses of LaC (750–2250 mg/day)(18). Although it is inappropriate to draw firm conclusions about the effect of long-term use of LaC on the plasma level of lanthanum since the dose of the present one year study was adjusted weekly between 750 mg and 4500 mg, there was not a huge increase in plasma lanthanum levels after seven months; therefore, LaC is unlikely to accumulate in the blood.
A one year treatment of lanthanum carbonate in patients with chronic kidney disease with hyperphosphatemia undergoing maintenance hemodialysis was well tolerated and effective in achieving and maintaining serum phosphate control within the clinical target range.
Acknowledgments: This research was supported by Bayer Yakuhin; however, the author has never had involvements that might raise the question of bias in the work reported, or in the conclusions, implications, or opinions stated.