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http://www.kidney-international.org & 2007 International Society of Nephrology

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Cognitive function in Stage 5 chronic kidney disease patients on hemodialysis: No adverse effects of lanthanum carbonate compared with standard phosphate-binder therapy P Altmann1, ME Barnett2,3 and WF Finn4, on Behalf of the SPD405-307 Lanthanum Carbonate Study Group 1

Oxford Kidney Unit, Oxford Radcliffe Hospitals NHS Trust and University of Oxford, Oxford, UK; 2Charles R Drew University, Los Angeles, California, USA; 3Barnett Research & Communications, Torrance, California, USA and 4Department of Medicine, University of North Carolina, Chapel Hill, North Carolina, USA

Patients with Stage 5 chronic kidney disease who have hyperphosphatemia require treatment with phosphate binders to lower serum phosphorus levels. Existing binders are effective but may be associated with important safety disadvantages. Lanthanum carbonate is a phosphate binder with demonstrated efficacy, safety, and tolerability in clinical trials. Changes in cognitive function were evaluated over time using the Cognitive Drug Research computerized cognitive assessment system (Simple Reaction Time, Digit Vigilance Task, Choice Reaction Time, Numeric Working Memory, and Delayed Picture Recognition) in 360 hemodialysis patients who were enrolled in a 2-year, multicenter, comparative study of lanthanum carbonate versus standard therapy. A decline in cognitive function from baseline was observed in both groups. The deterioration in cognitive function was similar in both the lanthanum carbonate and standard therapy groups. One parameter – Numeric Working Memory – showed a statistically significant between-group difference in favor of lanthanum carbonate (P ¼ 0.02). Given the magnitude of the changes, however, and the differences that were observed at baseline between treatment groups, the clinical significance of this difference is doubtful. This study demonstrates that cognitive function deteriorates in hemodialysis patients over a 2-year time period. Use of lanthanum carbonate as a phosphate binder does not adversely affect cognitive function compared with standard therapy. Kidney International (2007) 71, 252–259. doi:10.1038/sj.ki.5001932; published online 11 October 2006 KEYWORDS: phosphate binders; clinical trial; mineral metabolism; end-stage renal disease; hyperphosphatemia

Correspondence: P Altmann, Oxford Kidney Unit, Oxford Radcliffe Hospitals NHS Trust, Oxford OX3 7LJ, UK. E-mail: [email protected] Received 30 March 2006; revised 24 July 2006; accepted 29 August 2006; published online 11 October 2006 252

Hyperphosphatemia is a common complication seen in patients with Stage 5 chronic kidney disease (CKD). Uncontrolled hyperphosphatemia contributes to the development of secondary hyperparathyroidism, renal osteodystrophy, and vascular calcification. The latter has also been linked with an increased risk of cardiovascular mortality.1,2 To reduce serum phosphorus levels, patients are treated with phosphate-binding agents. A number of effective agents are currently available, but all have certain disadvantages. Calcium salts, including calcium carbonate and calcium acetate, are currently the mainstay of therapy, but recent evidence suggests that high doses of ingested calcium over prolonged periods of time are associated with hypercalcemia and vascular calcification.3,4 Sevelamer hydrochloride is a non-calcium, non-aluminum phosphate binder that has proven to be a useful addition to the current choices available. There are, however, some concerns, including gastrointestinal side effects, a tendency to metabolic acidosis, and a high pill burden.5,6 A number of new agents are currently being investigated but little is known about their long-term safety and tolerability.7,8 Aluminum hydroxide is the most potent phosphate binder that is currently available, but its toxic effects include brain disease, bone disease, parathyroid suppression, and anemia.9,10 The toxicity of aluminum in experimental animals was first observed in 1897,11,12 with the earliest report in 1921 outlining similar effects in industrially exposed workers.13 In 1976, the link between aluminum exposure and encephalopathy was first observed in dialysis patients.14 Abnormalities in psychomotor function related to aluminum status have been observed in hemodialysis patients even though they had no overt clinical signs of aluminum toxicity.15 Studies of the cognitive effects in dialysis patients are particularly relevant, as there is anecdotal evidence and crosssectional data to support a role for uremia and dialysis in reducing cognitive function.16–20 Longitudinal data are limited, although a study in elderly individuals found that Kidney International (2007) 71, 252–259

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P Altmann et al.: Lanthanum carbonate does not affect cognition

those with CKD (glomerular filtration rate o60 ml/min/ 1.73 m2) experienced a significantly greater decline in cognitive function compared with those with preserved renal function.20 In addition, it has been demonstrated that cognitive brain dysfunction in hemodialysis patients may be fully reversed by successful renal transplantation.16 Lanthanum carbonate (Fosrenols) is a phosphate binder that is effective and well tolerated in patients with Stage 5 CKD21–24 and has similar phosphate-binding potency to aluminum hydroxide (Damment SJP, Webster I, Presented at the 36th Annual Meeting of the American Society of Nephrology, San Diego, CA, USA, 2003). Importantly, the bioavailability of lanthanum (0.00089%)25 is substantially lower than that of aluminum (0.01%). There is no evidence from animal studies that lanthanum can cross the blood–brain barrier.26,27 In fact, the impermeability of a number of other blood–tissue barriers to lanthanum has also been demonstrated, including the placenta and retina.28,29 No functional or histopathological evidence of central nervous system toxicity of lanthanum has been identified in oral or intravenous studies with lanthanum carbonate in animals (Damment SJP, Greaves P, Downes N, Presented at the 36th Annual Meeting of the American Society of Nephrology, San Diego, CA, USA, 2003; Jones C, Webster I, Damment SJP, Presented at the 19th Congress of the ERA-EDTA, Lisbon, Portugal, 2004). Although brain lanthanum deposition has been reported recently in an animal model of renal failure,30 this finding has been challenged as a contamination artifact,31 as the mode of administration chosen (diet admixture) carried a high risk of sample contamination during autopsy. To allay fears about the potential for lanthanum to cause cognitive dysfunction in a similar manner to aluminum, we evaluated changes in cognitive function over time in hemodialysis patients who were receiving lanthanum carbonate or standard phosphate-binder therapy. RESULTS Patients

In total, 360 hemodialysis patients who were enrolled in the cognitive function subgroup were randomized (lanthanum carbonate, n ¼ 179; standard therapy, n ¼ 181) and performed at least one on-study cognitive function testing session. One hundred and thirty-three patients completed the full 2 years of treatment. One hundred and twenty-four patients (47 in the lanthanum carbonate group and 77 in the standard therapy group) completed all six cognitive function testing sessions. Notably, patient exposure was greater with standard therapy (512 days) than with lanthanum carbonate (366 days), as patients in the lanthanum carbonate group were required to withdraw if adverse events occurred or the investigator determined that additional therapy was required. Patients randomized to standard therapy could change to another approved phosphate binder or add additional binders and still remain in the study. Baseline characteristics and renal history are shown in Table 1. The lanthanum carbonate and standard therapy Kidney International (2007) 71, 252–259

groups were well matched at baseline, with the exception of a marginally higher proportion of Caucasian patients in the lanthanum carbonate group. The baseline scores for the Cognitive Drug Research (CDR) tests are presented in Table 2 as summary statistics of the major measures. The median plasma lanthanum level in all patients at screening was 0.0 ng/ml (range: 0.0–0.4 ng/ml). In patients randomized to lanthanum carbonate, this rose to 0.3 ng/ml (range: 0.0–3.1 ng/ml) by Week 7 and remained constant thereafter. In patients who were randomized to standard therapy, the median serum lanthanum level remained at 0.0 ng/ml (range: 0.0–2.7 ng/ml) throughout the study, except at Month 18, at which time the median lanthanum level was 0.1 ng/ml (range: 0.0–0.2 ng/ml). Concomitant medications

Before randomization, aluminum-based medications were used by 12 patients (7%) who were subsequently randomized to the lanthanum carbonate group and by eight patients (4%) Table 1 | Baseline characteristics and renal history Characteristic

Lanthanum carbonate (n=179)

Standard therapy (n=181)

54.4715.6

56.5714.1

104 (58) 75 (42)

109 (60) 72 (40)

Age, mean7s.d. (years) Gender, n (%) Male Female Race, n (%) Caucasian Black Hispanic Asian/Pacific Native American Other Weight, mean7s.d. (kg) Height, mean7s.d. (cm) Primary renal diagnosis, n (%) Diabetes Hypertension Glomerulonephritis Cystic kidney disease Urologic disease Unknown cause Other known cause

98 (55) 68 (38) 10 (6) 0 2 (1) 1 (1) 80.2722.4 169.9711.4

52 59 20 10 1 5 32

(29) (33) (11) (6) (1) (3) (18)

87 73 15 4 1 1

(48) (40) (8) (2) (1) (1)

80.8719.5 171.7710.9

62 44 26 10 4 3 32

(34) (24) (14) (6) (2) (2) (18)

Previous kidney transplant, n (%) No Yes

150 (84) 29 (16)

1678 (92) 14 (8)

Duration on hemodialysis (years) Median Range

2.82 0.4–19.4

2.37 0.4–21.8

Previous treatment, n (%) Calcium acetate Calcium carbonate Not listed Other therapy Sevelamer hydrochloride

76 50 1 7 44

(43) (28) (1) (4) (25)

75 60 3 6 37

(41) (33) (2) (3) (20) 253

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who entered the standard therapy group. Psychotropic drugs (e.g. antidepressants, antipsychotics or mood-stabilizing agents) were used by 85 patients (47%) who were subsequently randomized to the lanthanum carbonate group Table 2 | Baseline scores on the CDR tasks

Simple Reaction Time (ms) Mean 95% CI

Lanthanum carbonate (n=174)

Standard therapy (n=178)

378.0 362.2, 397.7

423.1 393.6, 452.5

Digit Vigilance – targets detected (%) Mean 92.7 95% CI 91.2, 94.2

90.7 88.7, 92.7

Digit Vigilance – response time (ms) Mean 486.2 95% CI 475.4, 497.1

503.5 491.6, 515.4

Digit Vigilance – false alarms (#) Mean 1.90 95% CI 1.54, 2.25

2.12 1.70, 2.55

Choice Reaction Time – accuracy (%) Mean 96.6 95% CI 95.9, 97.2

96.2 95.4, 97.0

Choice Reaction Time – response time (ms) Mean 600.2 95% CI 579.9, 620.5

641.8 614.4, 669.2

Numeric Working Memory – sensitivity Indexa Mean 0.88 95% CI 0.85, 0.90

0.83 0.80, 0.86

Numeric Working Memory – response time (ms) Mean 1067 95% CI 1011, 1122

1137 1073, 1201

Picture Recognition – sensitivity index Mean 0.59 95% CI 0.55, 0.62

0.54 0.50, 0.57

Picture Recognition – response time (ms) Mean 1377 95% CI 1301, 1452

1461 1380, 1541

and 69 patients (38%) who were randomized to the standard therapy group. During the study, aluminum-containing medications were used by 20 patients (11%) in the lanthanum carbonate group and by 20 patients (11%) in the standard therapy group. These medications included aluminum hydroxide and aluminum carbonate, and were generally prescribed over the short term for the treatment of dyspepsia, nausea, and chest pain, as well as for hyperphosphatemia. During the study, psychotropic drugs were used by 109 patients (61%) in the lanthanum carbonate group and 104 patients (58%) in the standard therapy group. Acetyl cholinesterase inhibitors, which are used for the maintenance of cognitive function in patients with Alzheimer’s disease, were used before and after randomization by two patients (1%) in the standard therapy group. At baseline, vitamin D and analogues were used by 42% of patients in the lanthanum carbonate group and 44% of patients in the standard therapy group. During the study, vitamin D and analogues were used by 39% of patients in the lanthanum carbonate group and 48% of patients in the standard therapy group. Results from mixed effect model for repeated measures

CDR, Cognitive Drug Research; CI, confidence interval; SI, sensitivity index. a SI combines the ability to identify previously presented items correctly and to reject those that were not previously presented. The score represents the overall ability of the patient to recognize (or be sensitive to) the task information (1=perfect discrimination; 0=chance performance).32

Differences in cognitive function between the two treatment arms (lanthanum carbonate and standard therapy) were noted at the baseline (screening) assessment (Table 2). This difference showed a uniform pattern of performance being consistently poorer in the standard therapy than in the lanthanum carbonate arm. This was seen both in longer reaction times in the standard therapy arm on each task and in poorer accuracy scores (sensitivity indices, percentage accuracy, and false-alarm scores). Cognitive function declined for most tests in both treatment groups over 2 years of treatment (Table 3, ‘Visit’ column). In addition, there were some other points of interest from these model fits. For the measure of Digit Vigilance – Targets Detected, there was a significant treatment-by-visit interaction (P ¼ 0.027; Table 3; Figure 1), indicating a different rate of decline between the two treatment groups. Although this interaction was influenced by a marked deterioration at the Final Visit in the standard therapy group, there were also greater deteriorations at Visits 9, 12, and 15 for standard therapy, which contributed to the

Table 3 | P-values from the mixed effect model Parameter Simple Reaction Time (ms) Digit Vigilance – targets detected (%) Digit Vigilance – response time (ms) Choice Reaction Time – response time (ms) Numeric Working Memory – sensitivity index (SI) Numeric Working Memory – response time (ms) Picture Recognition – SI Picture Recognition – response time (ms)

Treatmenta

Visitb

Treatment-by-Visit Interactionc

0.4520 0.0275* 0.6949 0.1681 0.1288 0.0243* 0.2911 0.7612

0.0024* 0.0141* 0.0001* 0.0001* 0.0886 0.1169 0.0372* 0.8701

0.2725 0.0269* 0.4772 0.0352* 0.6424 0.8846 0.2625 0.1646

*Statistically significant. a A significant treatment effect indicates a difference in overall effect between the two groups. b A significant visit effect indicates an overall change (deterioration in this case) over time. c A significant treatment by visit interaction indicates a different rate of decline between the two treatment groups.

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2

–20

Lanthanum carbonate

1

Standard therapy

Difference from baseline (ms)

0 –1

Difference from baseline (%)

Lanthanum carbonate Standard therapy

0

–2 –3 –4 –5 –6 –7 –8 –9

20 40 60 80 100 120 140

–10

160

–11 –12

180 Baseline

Visit 9

Visit 12

Visit 15

Visit 18

Final

0

3.5

6

12

18

24

Lanthanum carbonate (n) 174

153

121

89

63

47

Standard therapy (n)

153

143

121

93

77

Baseline

Visit 9

Visit 12

Visit 15

Visit 18

Final

0

3.5

6

12

18

24

Month


153

121

89

63

47


153

143

121

93

77

178

Figure 1 | Digit Vigilance Task – targets detected (%) (least-squares means795% CI from mixed effect model).

treatment effect. These comparisons supported a benefit for lanthanum carbonate over standard therapy at the Final Visit only and any interpretation of these differences should consider both differences at baseline and the differential completion rates between the treatment groups. There was no significant difference between the declines in Choice Reaction Time seen between the treatment groups (P ¼ 0.17; Figure 2), although there was a significant treatment-by-visit interaction (P ¼ 0.035). This was clearly a result of the difference between values at the Final Visit only. Accuracy scores showed little change over time (median: 0). Response time, measured in milliseconds (ms), increased (i.e. deteriorated) on the Numeric Working Memory task in both treatment groups. This decline was greater in the standard therapy group (Figure 3), with an overall significant treatment effect in favor of lanthanum carbonate (P ¼ 0.02). The magnitude of treatment difference was, however, small compared with the baseline between-group difference of 88 ms. A complete summary of results from the mixed effects model is presented in Table 3. DISCUSSION

Overall, this study shows that patients with Stage 5 CKD on hemodialysis who received either lanthanum carbonate or standard therapy experienced deterioration in cognitive function over 2 years. Notably, the impairments in cognitive function were generally related to the speed of task completion: whereas patients’ accuracy in completing the tests did not decline substantially, tests took longer to complete as the study progressed. The decline seen in the present study is consistent with previous studies that have shown significant impairments in cognitive function in patients with CKD compared with normal populations16–18 and the available longitudinal data showing that the decline Kidney International (2007) 71, 252–259

178

Figure 2 | Choice Reaction Time – response time (ms) (least-squares means795% CI from repeated mixed effect model).

–50

Lanthanum carbonate

–25

Standard therapy

0 Difference from baseline (ms)

Month

25 50 75 100 125 150 175 200 225 250 Baseline

Visit 9

Visit 12

Visit 15

Visit 18

Final

0

3.5

6

12

18

24


153

121

89

63

47


153

143

121

93

77

Month

178

Figure 3 | Numeric Working Memory – response time (ms) (least-squares means795% CI from mixed effect model).

in cognitive function over time is marked compared with that expected as a result of normal aging.20 For example, deterioration in patients receiving dialysis compared with healthy individuals has been reported in a cross-sectional study.16 Cognitive function in that study was assessed using visual-evoked potentials, which have previously been shown to correlate with the Symbol Digit Coding Test of psychomotor function.15 The level of deterioration was similar to that observed on the CDR assessment system in the present study.16 Moreover, the decline can be halted, and even reversed, by transplantation,16 suggesting a major role for uremia (and possibly the dialysis process itself) in the decline; however, factors such as vascular disease and subclinical Alzheimer’s disease cannot be ruled out. Importantly, cognitive decline in 255

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dialysis patients, which is not always appreciated by nephrologists in the clinic, can have an impact on issues such as the ability to remain employed, compliance with medication, decision-making, and attendance at clinic appointments. Despite the similarities in baseline demographic characteristics, baseline CDR response time measurements were statistically significantly better in the lanthanum carbonate group (e.g., for Choice Reaction Time, a difference of around 50 ms was observed). This could not have been the result of a breakdown in randomization, as the baseline CDR assessment was carried out during screening, before patients were randomized. In an attempt to explain this baseline difference, several factors that are known to affect cognitive function were investigated. At baseline, similar proportions of patients were receiving aluminum-based medications or active vitamin D (or analogues). A numerically higher percentage of patients in the lanthanum carbonate group were receiving psychotropic drugs at baseline, although agents such as diazepam and temazepam might be expected to have an adverse effect on cognitive function. Post hoc analysis of summary statistics separated by psychiatric medical history or by patients’ race did not explain the baseline difference (data not shown). Hematocrit values were also compared between groups in a post hoc analysis and were not considered to be clinically important (data not shown). There are a number of other possible explanations for a baseline difference in cognitive function, such as level of atherosclerosis, adequacy of dialysis, geographical differences, educational level, or socioeconomic effects. Insufficient data are available for exploratory analyses of these factors. However, the differences, along with the variability of the scores at baseline, are not considered to be clinically important and therefore would not have affected the outcomes of the study. Cognitive deterioration over time was the same in the lanthanum carbonate and standard therapy groups. The only parameter that has an independent significant difference between the treatment groups was Numeric Working Memory (P ¼ 0.02 in favor of lanthanum carbonate). This should, however, be interpreted with caution because the magnitude of treatment difference was small, when compared with the baseline between-group difference. In addition, significant treatment-by-time interactions were seen for Digit Vigilance (targets detected) and Choice Reaction Time (response time). These, however, appear to be spurious results that are related to the effects at a single time point that were not consistent throughout treatment. There have been conflicting reports about the extent to which lanthanum is able to cross the blood–brain barrier. In detailed electron microscopy studies in rats, lanthanum was unable to penetrate intercellular tight junctions or pass through the endothelial cells of the blood–brain barrier.26,27 Consistent with this, bulk brain lanthanum concentrations in various animal studies, measured using Inductively Coupled Plasma Mass Spectrometry (ICP-MS), were below quantifi256


able limits33 and toxicology studies identified no adverse effects of lanthanum carbonate treatment on brain function or histology (Damment SJP, Greaves P, Downes N, Presented at the 36th Annual Meeting of the American Society of Nephrology, San Diego, CA, USA, 2003; Jones C, Webster I, Damment SJP, Presented at the 19th Congress of the ERAEDTA, Lisbon, Portugal, 2004). Recently, Lacour et al.30 reported elevated levels of lanthanum in an adenine rat model of chronic renal failure. Surprisingly, no increase in brain concentration occurred after treatment with lanthanum carbonate in an alternative renal failure model (5/6th nephrectomized) or in normal rats in the same study, both of these groups having numerically lower brain concentrations compared with their respective untreated controls. Subsequently, the findings of this study have been challenged as a contamination artifact.31 Lanthanum carbonate was offered to the rats in a powdered diet at 3% w/w, and thus entered the animals’ environment at concentrations at least six orders of magnitude higher than in normal brain, presenting a high risk of tissue contamination at autopsy, whereas lanthanum in previous studies was gavaged directly into the stomach of the rats. The computer-controlled tasks from the CDR cognitive assessment system chosen for the present study are those focusing on attention, working memory, and reaction time, and it should be noted that their ability to assess episodic memory and other aspects of cognition are limited. Indeed, memory is often tested through the use of multiple learning trials and free recall trials. The effects of dialysis treatment on other aspects of cognitive function such as list learning or symbol digit replacement are not well studied. The CDR tests are sensitive measures of psychomotor function that are more appropriate for investigational studies than for routine clinical use. A number of groups have investigated simpler methods of assessing cognitive function that are appropriate for dialysis patients. One such method is the Kidney Disease Quality of Life Cognitive Function Subscale. This is a selfreport measure that includes a 36-item health survey as the generic core, supplemented with scales that are targeted at particular concerns of individuals with kidney disease and receiving dialysis. In a validation study in patients with CKD, a high level of correlation was demonstrated between the Kidney Disease Quality of Life Cognitive Function Subscale and the modified Mini-Mental State Examination (MMSE).19 The modified MMSE is considered to be more sensitive than the traditional MMSE, especially for mild cognitive change. The modified MMSE incorporates four added test items, more graded scoring, and other minor changes. These modifications are designed to sample a broader variety of cognitive functions, cover a wider range of difficulty levels, and enhance the reliability and the validity of the scores.34 As reported elsewhere,35 when the MMSE was administered to dialysis patients receiving either lanthanum carbonate or standard therapy, the mean score on the MMSE at baseline was 28.4 (a normal MMSE score is considered to be 424) in both treatment groups, and no changes were seen over 2 years Kidney International (2007) 71, 252–259

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of treatment. Although normal in this study, the MMSE has been found to be abnormal when broadly applied to hemodialysis patients.36,37 As a tool for assessing cognitive function in selected groups of patients, however, the MMSE is not sufficiently discriminatory. This emphasizes the need for further refinement of tools for assessing cognitive impairment in CKD. As these defects may be at least partially reversible,16 appropriate treatment of cognitive function deterioration may be possible. This applies to patients with CKD Stages 3 and 4, as well as those with Stage 5 CKD receiving hemodialysis.17 Among the abnormalities that are thought to be responsible for the defects in cognition, cerebrovascular disease,18 anemia,38 and disorders of mineral metabolism39 stand out. Conclusions

Hemodialysis patients who were treated with lanthanum carbonate and standard phosphate binders showed deterioration in cognitive function during 2 years of follow-up. This deterioration was marked compared with normal aging and was independent of the phosphate-binder therapy that was used. There is no known mechanism for lanthanum to cross

the blood–brain barrier, and no toxic effects of lanthanum in brain or other tissues have been observed in studies of animals exposed to large doses of lanthanum. Thus, it seems unlikely that lanthanum carbonate poses a similar threat of neurotoxicity to that observed with the far more readily absorbed aluminum from aluminum-hydroxide-containing phosphate binders. Lanthanum carbonate remains effective and well tolerated for the treatment of patients with hyperphosphatemia in Stage 5 CKD. MATERIALS AND METHODS Study design Cognitive function assessment was conducted at 41 sites in the USA in a subgroup of hemodialysis patients from a 2-year, randomized, open-label comparator study of lanthanum carbonate versus standard therapy.35 The study comprised three phases: screening and a 1–3-week washout period of previous phosphate binders; a 6-week dose titration period; and long-term maintenance (up to 2 years’ total study participation). Patients were randomized 1:1 to receive lanthanum carbonate or their pre-study phosphate binder. Lanthanum carbonate treatment was started at a dose of 750 or 1500 mg/day, at the discretion of the investigator. The dose could be titrated up to 3000 mg/day or down to 375 mg/day, as necessary.

Table 4 | List of CDR assessments Task

Supporting measurea

Description

Major measure

The patient was instructed to press the ‘YES’ response button as quickly as possible every time the word ‘YES’ was presented on the monitor. Thirty stimuli were presented at varying interstimulus intervals.

Response time (ms)

Digit Vigilance

A target digit was randomly selected and constantly displayed to the right of the monitor screen. A series of digits was presented in the center of the screen at the rate of 150 per minute, and the patient was required to press the ‘YES’ button as quickly as possible every time the digit in the series matched the target digit. In total, 450 digits, including 45 targets, were presented over 3 min.

Response time (ms) Targets detected (%)

False alarms (#)

Choice Reaction Time

Either the word ‘NO’ or the word ‘YES’ was presented on the monitor and the patient was instructed to press the corresponding button as quickly as possible. Thirty trials were chosen randomly with equal probability, and were presented at varying interstimulus intervals.

Response time (ms)

Accuracy (%)

A series of five digits was presented for the patient to remember, followed by a series of 30 probe digits. For each digit, the patient indicated whether or not they recognized it as being from the original series by pressing the ‘YES’ or ‘NO’ button as appropriate.

Sensitivity index (SI)b Response time (ms)

Attentional Tasks: Simple Reaction Time

Working Memory Task: Numeric Working Memory

Episodic Secondary Memory Task: Picture Recognition Before the Simple Reaction Time test, a series of 20 pictures was presented on the monitor at the rate of one every 3 seconds for the patient to remember. In the Picture Recognition test, the original pictures, plus 20 distracter pictures, were presented one at a time in a randomized order. For each picture, the patient indicated whether or not they recognized it as being from the original series by pressing the ‘YES’ or ‘NO’ button as appropriate.

Sensitivity index (SI)b Response time (ms)

a

Analysis of covariance was not carried out on the supporting measures. SI combines the ability to identify previously presented items correctly and to reject those that were not previously presented. The score represents the overall ability of the patient to recognize (or be sensitive to) the task information (1=perfect discrimination; 0=chance performance).32

b


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Patients in the standard therapy group could switch or add other phosphate binders at the discretion of the investigator throughout the study.


were randomized and had at least one post-randomization phosphorus measurement in the main study. ACKNOWLEDGMENTS

Patients All patients were 18 years of age or older and had received hemodialysis three times per week for Stage 5 CKD for at least 2 months before enrolment. All patients were judged by the investigator to have the initiative, health, and means to be compliant with the study protocol. Patients were excluded if they had clinically significant abnormal laboratory values at screening, unless they were considered to be a consequence of Stage 5 CKD. Patients receiving psychotropic drugs who had been stabilized for less than 1 month were also excluded. Other exclusion criteria included documented aluminum-related bone disease or dementia, a screening calcium level below 7.9 mg/dl (1.98 mmol/l), evidence of previous gastrointestinal surgery or ongoing gastrointestinal disorders, levels of serum transaminases more than three times the upper limit of normal, life-threatening malignancy or current multiple myeloma, known HIV-positive status, or exposure to an experimental drug within 30 days before screening. Pregnant or lactating women, and women of reproductive potential, who did not agree to use effective birth control methods, were also excluded. Assessments Cognitive function was assessed using computer-controlled tasks from the CDR cognitive assessment system (Table 4). This method was chosen because a reproducible and objective assessment of cognitive function could be quickly administered by a research nurse. Information was presented on high-resolution monitors, and responses were recorded via response modules containing two buttons, one marked ‘NO’ and the other marked ‘YES’. During the screening period, patients received two training sessions, each consisting of two administrations of the testing system. Patients who did not successfully complete the training sessions after two attempts were excluded from the study, whereas those patients who completed the training then received a baseline assessment. Testing was performed before dialysis at the second or third dialysis session of the week. Tests were carried out at screening (prerandomization/baseline), 3.5 months (Visit 9), 6 months (Visit 12), 12 months (Visit 15), 18 months (Visit 18), and 24 months (Final Visit). For patients who terminated the study early, the last testing session was included in the appropriate time category, rather than as Final Visit. Patients were recruited for the cognitive function sub-study before randomization into a treatment group in an attempt to avoid potential bias. The tests were conducted in the order outlined in Table 4. The first three tasks were tests of the patient’s attention span; the last two tasks were tests of the patient’s memory. Analysis Summary statistics were calculated for each measure and each timepoint by treatment. For each of the major measures, a mixed effects model for repeated measures was used to examine the difference from baseline data. Fixed terms in the model were treatment, timepoint and treatment-by-time-point interaction. A random effect of subjects-within-treatment was included in the model and baseline score was used as a covariate. Analyses were conducted on the intent-to-treat population, which was defined as all patients who 258

We thank the following investigators for their contributions to the SPD405-307 clinical study. This study was funded by Shire Pharmaceuticals. United States: Ahmer H Qarni, Fargo, ND; Ali Iranmanesh, Salem, VA; Allan Sklar, Binghamton, NY; Allen Lauer, Brockton, MA; Ashraf Selim, Malden, MA; Barry Lankhorst, Sioux Falls, SD; Barry Miskin, West Palm Beach, FL; Beckie Michael, Philadelphia, PA; Bernard Michlin, San Diego, CA; Brian N Ling, Asheville, NC; Bruce Spinowitz, Flushing, NY; Clyde Pence, Pensacola, FL; Dan Koenig, Raleigh, NC; David Van Wyck, Tucson, AZ; Debesh Mazumdar, New Berlin, WI; Denise Ricker, San Pablo, CA; Donald Sherrard, Seattle, WA; Douglas T Domoto, St Louis, MO; Duane G Wombolt, Norfolk, VA; Earl Dunnigan, Bismark, ND; Edward Frederickson, Conyers, GA; Edward Tokatlian, Phoenix, AZ; Eileen Cook, Austin, TX; Emil Skobeloff, Ridley Park, PA; Fred L Smardo, Fayetteville, AR; Fredrick Osorio, Ventures Mesa, AZ; Fredrick Rogoff, Greer, SC; George M Nassar, Houston, TX; Gerald Keightley, Richmond, VA; Ghada Bourjeily, Tiverton, RI; Ghodrat A Siami, Nashville, TN; Hanna Mawad, Lexington, KY; Harold Locay, Ocala, FL; Hartmut Malluche, Lexington, KY; Howard Hassman, Clementon, NJ; Jacinto Hernandez, Memphis, TN; Jack Moore, Washington, DC; James Kopp, Anderson, SC; James L Lewis, Birmingham, AL; James Pederson, Oklahoma City, OK; Jeffrey B Rosen, Coral Gables, FL; Jesus Navarro, Tampa, FL; Jill Lindberg, New Orleans, LA; John D Anthony, Missoula, MT; John Ervin, Kansas City, MO; John G Elder, Santa Barbara, CA; John Middleton, Dallas, TX; Jose Cangiano, San Juan, PR; K Adu Ntoso, Philadelphia, PA; Karl Brinker, Dallas, TX; Keith Kapatkin, Brandon, FL; Kenneth Boren, Mesa, AZ; Kenneth Fisher, Detroit, MI; Kenneth Kleinman, Encino, CA; Lakshmi Natarajan, New Port Ritchey, FL; Laura L Mulloy, Augusta, GA; Leland Garrett, Raleigh, NC; Leslie Steed, Portland, OR; Lois A Katz, New York, NY; M Edwina Barnett, Torrance, CA; Marc S Weinberg, Providence, RI; Mark R Kaplan, Nashville, TN; Martin Topiel, Mount Laurel, NJ; Mary J Shaver, Little Rock, AR; Michael Anger, Thornton, CO; Michael Bierle, Little Rock, AR; Michael Germain, West Springfield, MA; Michael Koren, Jacksonville, FL; Michel Chonchol, Denver, CO; Muralidhar Acharya, Newport Richey, FL; N Martin Lunde, Arden Hills, MN; Phillip Marin, Grand Forks, ND; Pran Kar, Orlando, FL; Rajnish Mehrotra, Torrance, CA; Ramesh Soundararajan, Canfield, OH; Remegio Vilbar, Chicago, IL; Richard Bilinsky, Springfield, IL; Richard Coalson, Beavercreek, OH; Richard Halterman, Boulder, CO; Richard S Kebler, Bend, OR; Robert A Moore, Wilmington, NC; Robert Lynn, Bronx, NY; Robert McCrary, Little Rock, AR; Robert Mossey, Great Neck, NY; Robert Tomford, Olympia, WA; Ronald Crock, Canton, OH; Saied Murphy, Atlanta, GA; Sergio Acchiardo, Memphis, TN; Stephen Rifkin, Brandon, FL; Steven G Rosenblatt, San Antonio, TX; Steven Zeig, Pembroke Pines, FL; Suhail Ahmad, Seattle, WA; Suzanne Swan, Minneapolis, MN; Theodore Herman, Amherst, NY; Thomas C Marbury, Orando, FL; Thomas Martin, Tacoma, WA; Thomas Rakowski, Arlington, VA; Thomas Tucker, Brunswick, GA; Vaughn W Folkert, Bronx, NY; Wayne Rodriguez, Melbourne, FL; William B Smith, New Orleans, LA; William Finn, Chapel Hill, NC; William Klein, Wyomissing, PA; Wolfgang J Weise, Burlington, VT. South Africa: Alain Assounga, Durban; Charles Swanepoel, Cape Town; Rafik Moosa, Cape Town; Sarala Naicker, Gauteng. Poland: Marian Klinger, Wroclaw; Waldysaw Sulowicz, Cracow. REFERENCES 1.

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