SVCARB00205: A randomised, cross-over study to demonstrate equivalence of sevelamer carbonate powder and sevelamer hydrochloride tablets dosed three times per day in haemodialysis patients

Renvela^® (sevelamer carbonate)

Drug Name	Generic Name	Studied Indications or Disease	Approved U.S. Drug Label
Renvela	Sevelamer Carbonate	Hyperphosphatemic Chronic Kidney Disease	Prescribing Info

These results are supplied for informational purposes only.
Prescribing decisions should be made based on the approved package insert

NAME OF SPONSOR/COMPANY

Genzyme Corporation, 500 Kendall Street, Cambridge, Massachusetts, 02142

INVESTIGATORS AND STUDY CENTER(S)

This was a multicenter study conducted at 7 centres in the United Kingdom (UK).

PUBLICATION (REFERENCE)

Publications

STUDIED PERIOD

First Patient Enrolled: 31 January 2006
Last Patient Completed: 21 March 2007

PHASE OF DEVELOPMENT

Phase 3

OBJECTIVES

Objectives:

Primary Objectives

In hyperphosphatemic chronic kidney disease (CKD) patients on haemodialysis (HD):

Secondary Objectives

In hyperphosphatemic CKD patients on HD, to compare the effects of sevelamer carbonate powder to sevelamer hydrochloride tablets when dosed TID with meals on:

METHODOLOGY

This was a Phase 3, multi-centre, open-label, randomised, cross-over study that consisted of 6 periods: a 2-week Screening and Washout Period, a 4-week sevelamer hydrochloride tablet Run-In Period, a 4-week Treatment Period (Treatment Period 1), a second 4-week Treatment Period (Treatment Period 2 when the alternative study medication was taken), and a Follow-up visit 1 week after the last study treatment visit.

Eligible patients were asked to discontinue their current phosphate binder(s) and enter a 2-week Washout Period. At the end of the Washout Period, patients who were hyperphosphatemic (serum phosphorus ≥ 5.5 mg/dL or ≥ 1.76 mmol/L) continued into the 4-week Run-In Period. Each patient’s binder dose taken prior to the Washout Period was replaced with an equivalent number of 800 mg tablets of sevelamer hydrochloride (not to exceed a total daily dose of 14.4 g or 18 x 800 mg tablets). Patients had weekly visits during the Run-In Period. The dose of sevelamer hydrochloride tablets could be adjusted if necessary at Visits 3 and 4 (Weeks -3 and -2) to keep serum phosphorus levels within a target level of 3.5 and 5.5 mg/dL (1.12 and 1.76 mmol/L), inclusive, by increasing or decreasing by 1 x 800 mg tablet TID (2.4 g/day).

Patients eligible to continue into the treatment period maintained the dose of study drug that was last prescribed during the Run-In Period for the remainder of the study. At Baseline (Visit 6, Week 0), eligible patients were randomised one of two treatment sequences:

The prescribed dose during the two randomised treatment periods was individualised based on the final sevelamer hydrochloride tablet dose prescribed at the end of the Run-In Period prior to randomisation. Study medication was discontinued at the end of Treatment Period 2 and Follow-Up visit was 7 days later.

Number of Patients (planned and TREATED):

Number randomized (planned): 24
Number randomized/treated: 31/31
Number Completed: 24

NUMBER OF PATIENTS (ANALYZED):

Number in Full Analysis Set (FAS): 30
Number in Per Protocol Set (PPS): 21

DIAGNOSIS AND MAIN CRITERIA FOR INCLUSION

Adult patients, on a stable haemodialysis regimen three times weekly for 3 months or longer and receiving sevelamer hydrochloride alone or on combination therapy not exceeding a total daily binder dose of 14.4 g, for at least 60 days prior to screening; with recent serum phosphorus measurements that were ≥ 3.0 and ≤ 7.0 mg/dL (≥0.96 and ≤2.26 mmol/L), iPTH measurement ≤ 900 pg/mL (≤99 pmol/L), and serum calcium (adjusted for albumin) measurement within normal range defined by the local laboratory.

Patients also had a serum phosphorus measurement ≥ 5.5 mg/dL (≥1.76 mmol/L) at Visit 2 (after Washout), a serum iPTH measurement ≤ 800 pg/mL (88 pmol/L) at Visit 5 (prior to randomisation) and a serum phosphorus measurement ≥ 3.0 and ≤ 6.5 mg/dL (≥0.96 and ≤2.08 mmol/L) at Visit 5.

TEST PRODUCT, DOSE, AND MODE OF ADMINISTRATION

Sevelamer carbonate powder, 800 mg in sachets to be mixed with water and taken orally TID with meals. The starting dose during the two randomised treatment periods was individualised based on the final sevelamer hydrochloride tablet dose prescribed at the end of the Run-In Period prior to randomisation.

DURATION OF TREATMENT

The total treatment duration was 8 weeks (two 4-week randomised treatment periods):

Or

REFERENCE THERAPY, DOSE AND MODE OF ADMINISTRATION

Sevelamer hydrochloride, 800 mg tablets for oral administration. The starting dose during the two randomised treatment periods was individualised based on the final sevelamer hydrochloride tablet dose prescribed at the end of the Run-In Period prior to randomisation.

CRITERIA FOR EVALUATION
Efficacy:

The treatment regimens were compared on the basis of serum phosphorus at the end of each treatment period using the time-weighted mean of the phosphorus values from the last two weeks in each 4-week randomised treatment period. The treatment regimens were also compared with respect to calcium-phosphorus product using the same method.

The treatment regimens were compared with respect to effects on lipid parameters (total cholesterol, HDL cholesterol, LDL cholesterol and triglycerides) using the laboratory assessment at the end of each randomised treatment period.

Safety:

Safety was evaluated on the basis of AEs (reported and/or observed), changes in clinical laboratory evaluations and physical examination/vital signs (systolic and diastolic blood pressure, heart rate, and respiratory rate). Clinically significant changes in laboratory parameters, physical examination findings and vital signs were recorded and evaluated as AEs.

STATISTICAL METHODS

EFFICACY:
The effects of sevelamer carbonate powder and sevelamer hydrochloride tablets, each dosed TID with meals, on the control of serum phosphorus was determined using equivalence testing. The primary analysis was performed on the PPS to minimise the degree of bias. FAS analysis was performed as a confirmatory analysis. The time-weighted average of the serum phosphorus assessments from the last four visits during the last two weeks of each treatment regimen (mean of non-missing assessments from Weeks 3, 3a, 4, and 4a for Treatment Period 1 and mean of non-missing assessments from Weeks 7, 7a, 8, and 8a for Treatment Period 2) was used to give a more accurate assessment of phosphorus control than would be attained by a single point reading. Equivalence was assessed using natural-log transformed time-weighted mean serum phosphorus data. Least squares means for each treatment and the mean squared error from a 2x2 analysis of variance (ANOVA) with a random subject effect and fixed sequence, period, and treatment effects were used to derive the 90% confidence interval for the difference between powder (test) and tablet (reference) data on the log scale. Back transformation to the original scale yielded an estimate of the ratio (test/reference) and corresponding 90% confidence interval which was the basis of a 5% Two One-Sided Test (TOST) equivalence test. This test required that the 90% confidence interval for the ratio was within the interval (0.80, 1.25). If the sequence effect was significant (p-value ≤ 0.05), then equivalence inferences were to be drawn from the Treatment Period 1 results.

To assess the differences between sevelamer carbonate powder and sevelamer hydrochloride tablets, each dosed TID with meals, on serum calcium-phosphorus product, total cholesterol, HDL cholesterol, LDL cholesterol and triglyceride levels, a 2x2 ANOVA model based on natural-log transformed data with a random subject effect and fixed sequence, period, and treatment effects was used. Comparisons between the treatment regimens were tested at the 5% level. In addition, the geometric least squares means ratio and corresponding 90% confidence intervals were derived as described for the primary efficacy parameter to provide a relative sense of magnitude of any difference that was observed. These secondary analyses were performed using the FAS with supporting analysis using the PPS.

SAFETY:
AEs were coded using the standardised Medical Dictionary for Regulatory Activities (MedDRA) version 9.1. During the Run-In Period, all AEs, SAEs, and treatment-related events were summarised overall and by treatment sequence for each System Organ Class (SOC) and Preferred Term (PT). During randomised treatment, all AEs, SAEs, and treatment-related events were tabulated by SOC and PT by study treatment overall. AEs were also summarised by severity, in which a patient’s most severe event within a category (e.g., treatment regimen, SOC, PT) was counted. No statistical testing was planned or conducted.

Changes in laboratory values from Baseline (end of hydrochloride Run-In Period at Week 0) to the end of the treatment period were summarised by study treatment, both overall and by treatment sequence. Treatment regimens were compared overall using the Wilcoxon signed rank test, while within treatment regimen changes were also assessed using the Wilcoxon signed rank test.

Changes in vital signs from Baseline (Week 0) to the end of the treatment period were summarised by study treatment, both overall and by treatment sequence. Treatment regimens were compared overall using the Wilcoxon signed rank test, while within treatment regimen changes were also assessed using the Wilcoxon signed rank test.

SUMMARY / CONCLUSIONS

Demographics and Renal History

In the Safety Set, 21 (68%) patients were male and 10 (32%) patients were female, with a mean age of 53 years. The majority of patients were Caucasian (71%), with Asians (19%) and Blacks (10%) comprising the rest of the population. The most common primary causes of CKD were glomerulonephritis (26%), diabetes (13%) and “other” causes (42%). Patient demographics and renal history was well balanced between treatment sequences.

Efficacy

In the PPS, the mean serum phosphorus was 5.0 ± 1.5 mg/dL (1.6 ± 0.5 mmol/L) during sevelamer carbonate powder treatment and 5.2 ± 1.1 mg/dL (1.7 ± 0.4 mmol/L) during sevelamer hydrochloride tablet treatment. The geometric least square mean ratio (sevelamer carbonate powder/sevelamer hydrochloride tablets) was 0.95 with a corresponding 90% confidence interval of 0.87-1.03. The confidence interval is within the interval of 0.80-1.25, indicating that sevelamer carbonate powder and sevelamer hydrochloride tablets, each dosed TID with meals, are equivalent in controlling serum phosphorus.

In the FAS, the mean serum phosphorus was 5.0 ± 1.5 mg/dL (1.6 ± 0.5 mmol/L) during sevelamer carbonate powder treatment and 5.1 ± 1.1 mg/dL (1.7 ± 0.4 mmol/L) during sevelamer hydrochloride tablet treatment. The geometric least square mean ratio (sevelamer carbonate powder/sevelamer hydrochloride tablets) was 0.96 with a corresponding 90% confidence interval of 0.88-1.05. The confidence interval is within the interval of 0.80-1.25, indicating that sevelamer carbonate powder and sevelamer hydrochloride tablets, each dosed TID with meals, are equivalent in controlling serum phosphorus.

In the FAS, the mean serum calcium (albumin-adjusted)-phosphorus product was 45.9 ± 13.8 mg²/dL² (3.7 ± 1.1 mmol²/L²) during sevelamer carbonate powder treatment and 45.8 ± 10.0 mg²/dL² (3.7 ± 0.8 mmol²/L²) during sevelamer hydrochloride tablet treatment. No statistically significant differences were observed between sevelamer carbonate powder and sevelamer hydrochloride tablets with regards to serum calcium (albumin-adjusted)-phosphorus product. The geometric least square mean ratio (sevelamer carbonate powder/sevelamer hydrochloride tablets) was 0.98 with a corresponding 90% confidence interval of 0.88-1.09, which is within the 0.80-1.25 interval.

In the FAS, mean lipid levels at the end of treatment with sevelamer carbonate powder and sevelamer hydrochloride tablets, respectively, were:

No statistically significant differences were observed between sevelamer carbonate powder and sevelamer hydrochloride tablets with regards to lipid levels at the end of each treatment period. For each lipid parameter, the 90% confidence interval of the sevelamer carbonate powder/sevelamer hydrochloride tablets geometric least squares mean ratio was within the 0.80-1.25 interval.

Safety Results:

The mean actual dose during the randomised treatment periods was 5.9 ± 2.7 g/day of sevelamer carbonate powder and 6.5 ± 3.3 g/day of sevelamer hydrochloride tablets.

Adverse experiences

During the sevelamer hydrochloride tablet 4 week Run-In Period, a total of 44 AEs were reported in 19 (61.3%) of the 31 patients in the Safety Set. The highest frequency of AEs during Run-In occurred in the MedDRA SOC of Gastrointestinal Disorders with 17 events occurring in 11 (35.5%) patients. The most frequently occurring gastrointestinal AEs during the Run-In Period were (by MedDRA PT) dyspepsia (4 events in 3 [9.7%] patients), diarrhoea (3 events in 2 [6.5%] patients) and nausea (2 events in 2 [6.5%] patients). The majority of AEs during the Run-In Period were of mild or moderate intensity. Two severe AEs (one event of hypotension and one event of dyspepsia) were reported in 2 of the 31 randomised patients during the Run-In Period: neither event was considered by the investigator to be related to sevelamer hydrochloride. A total of 9 events in 7 (22.6%) of the 31 randomised patients were considered by the investigator as treatment-related during the sevelamer hydrochloride Run-In Period. All treatment-related AEs during the Run-In Period were coded to the Gastrointestinal Disorders SOC. Dyspepsia (3 events in 2 [6.5%] patients) was the most frequently reported related AE; all other related AEs were single events reported in single patients. During the Run-In Period, 1 SAE (streptococcal sepsis) was reported in 1 (3.2%) of the 31 randomised patients; the SAE was considered by the investigator as not related to sevelamer hydrochloride.

The overall frequency of AEs that started or worsened during the open-label, 4 week randomised treatment periods was similar between treatment regimens: 21 events in 10 (32.3%) patients during treatment with sevelamer carbonate powder and 26 events in 12 (42.9%) patients during treatment with sevelamer hydrochloride tablets. In general, AEs were reported across SOCs and during both treatment regimens the majority of AEs occurred as single events in single patients. The AE reported in more than one patient during sevelamer carbonate powder treatment was nausea (2 events in 2 [6.5%] patients). The events reported in more than one patient during treatment with sevelamer hydrochloride tablets were fatigue and arteriovenous fistula operation, each reported as 2 events in 2 (7.1%) patients. The majority of AEs were mild or moderate in intensity. One severe AE (chest pain) was reported in 1 (3.2%) patient during sevelamer carbonate powder treatment and no severe AEs were reported in patients during sevelamer hydrochloride tablet treatment.

The frequency of treatment-related AEs during the open-label, randomised treatment periods was low: a total of 4 events in 3 (9.7%) patients were considered by the investigator to be treatment-related. All related AEs were reported during treatment with sevelamer carbonate powder and were coded to the Gastrointestinal Disorders SOC: nausea (2 events in 2 [6.5%] patients), constipation (1 event in 1 [3.2%] patient) and vomiting (1 event in 1 [3.2%] patient). All treatment-related AEs were of mild or moderate intensity.

No patients died during the period from Screening through to the end of the 1-week Follow-up Period. One patient died due to brain stem haemorrhage during the 30-day post-completion period; the death was considered as not related to study treatment by the investigator. Two patients experienced SAEs during the 30-day post completion period.  One patient experienced an SAE of fluid overload, one patient experienced SAEs of fluid overload, headache and vomiting.  The frequency of SAEs was low in each treatment regimen during the open-label, randomised treatment periods: 2 SAEs (1 event each of catheter sepsis and chest pain) in 2 (6.5%) patients during treatment with sevelamer carbonate powder and 2 SAEs (2 events of catheter related complication) in 1 (3.6%) patient during treatment with sevelamer hydrochloride tablets. No SAEs were considered by the investigator to be related to study treatment.

Three (9.7%) of the 31 randomised patients experienced a total of 4 AEs leading to discontinuation of study medication: all 3 patients discontinued during treatment with sevelamer carbonate powder. Three of the 4 events leading to discontinuation were non-serious events coded to the Gastrointestinal Disorders SOC: 2 events of nausea and 1 event of vomiting. The other event leading to discontinuation was an SAE of chest pain.

Laboratory values and vital signs

During sevelamer carbonate powder treatment, there was a statistically significant increase from the end of the Run-In period to the end of treatment in serum bicarbonate (mean change 2.7 mEq/L; p=0.001) and a statistically significant decrease in serum chloride (mean change –2.7 mEq/L; p<0.001); no statistically significant mean changes were observed in these parameters during sevelamer hydrochloride treatment. The observed mean change in serum bicarbonate and serum chloride was statistically significantly different between treatment regimens (p=0.001 and p<0.001, respectively).

Other statistically significant changes in laboratory parameters included statistically significant decreases in BUN, creatinine, white blood cells, red blood cells, haemoglobin, haematocrit, and eosinophils during treatment with sevelamer carbonate powder, and a statistically significant increase in iPTH during sevelamer hydrochloride tablet treatment. Of these changes in laboratory parameters, only the increase in serum bicarbonate during treatment with sevelamer carbonate powder was considered clinically meaningful.

There were no statistically significant changes in vital signs for either treatment regimen, and no statistically significant differences in vital sign changes between treatment regimens.

Conclusion

This study demonstrated that sevelamer carbonate powder and sevelamer hydrochloride tablets, each dosed TID with meals, were equivalent in controlling serum phosphorus in CKD patients on HD. Serum calcium (albumin-adjusted)-phosphorus product and lipid profiles were comparable between treatment regimens. Sevelamer carbonate powder and sevelamer hydrochloride tablets have a similar safety profile when dosed TID with meals.