SVCARB00105: An Open Label, Dose Titration Study Of Sevelamer Carbonate Tablets Dosed Three Times A Day In Hyperphosphatemic Chronic Kidney Disease Patients Not On Dialysis

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)

A total of 25 centers participated in this study; 20 investigative sites in Europe and 5 in Australia. Nineteen of the 25 sites (15 in Europe and 4 in Australia) enrolled patients.

PUBLICATION (REFERENCE)

Publications

STUDIED PERIOD

First Patient Enrolled: 14 February, 2006
Last Patient Last Visit: 23 January, 2007

PHASE OF DEVELOPMENT

Phase 3

OBJECTIVES

Objectives:

Primary Objectives:

In hyperphosphatemic chronic kidney disease (CKD) patients not on dialysis:

Secondary Objectives:

In hyperphosphatemic CKD patients not on dialysis, evaluate sevelamer carbonate tablets dosed TID with meals on the following:

Percent responders (serum phosphorus between 2.7 mg/dL and 4.6 mg/, inclusive) at Day 56/early termination (ET)

METHODOLOGY

This was an open label, single-arm, dose titration study of hyperphosphatemic CKD patients not on dialysis. The study consisted of a 2-week screening period, a 2-week pre-treatment washout period, an 8-week treatment period and a 2-week post-treatment washout period. The initial 2-week washout period was only applicable for those eligible patients taking phosphate binder(s) at screening. Eligible patients who were not taking phosphate binder(s) at screening proceeded directly to the start of the 8-week treatment period. Patients with a serum phosphorus level ≥ 5.5 mg/dL either at screening or after washout, as applicable, and who met all other entry criteria were eligible for study treatment.

Patients started treatment with sevelamer carbonate at a dose of 4.8 g daily (2 x 800 mg tablets TID). The sevelamer carbonate dose was titrated to a maximum dose of 12 g/day (15 x 800 mg tablets) during the treatment period in increments of 2.4 g daily (1 x 800 mg tablet TID) at visits on Days 14, 28, and 42 to attain a target serum phosphorus level ≥ 2.7 mg/dL and ≤ 4.6 mg/dL.

In addition to receiving sevelamer carbonate, patients were supplemented with a daily oral dose of 400 IU of vitamin D to minimize the effects of any dietary absorption of vitamin D that may occur during treatment with sevelamer carbonate; this was to be taken at bedtime away from the dose of sevelamer carbonate. This supplement was to be given in addition to any active vitamin D therapy routinely prescribed at the start of the study.

A second phosphate binder washout phase followed the active treatment period to establish the degree of efficacy, after which patients were returned to their prior therapy. Throughout the study, patients were not to make any intentional changes in their diet and were not to be started on treatment with 1, 25 dihydroxyvitamin D, and/or cinacalcet or lipid-lowering medications. If prescribed these medications before study initiation, the dose was to be maintained.

NUMBER OF PATIENTS (PLANNED AND ANALYZED)

Number Enrolled / Treated: 129/ 49
Number Completed: 41.

DIAGNOSIS AND MAIN CRITERIA FOR INCLUSION

Patients included in this study were men and women, 18 years or older with a serum phosphorus level ≥ 5.5 mg/dL either at screening (for patients not on a phosphate binder) or after washout (for patients taking a phosphate binder) with 25-hydroxy vitamin D measurement of ≥10 ng/mL and an intact parathyroid hormone (iPTH) measurement of ≤800 pg/mL.

TEST PRODUCT, DOSE, AND MODE OF ADMINISTRATION

sevelamer carbonate: 800 mg tablets administered orally

DURATION OF TREATMENT

Patients were treated with sevelamer carbonate for up to 8 weeks.

REFERENCE THERAPY, DOSE AND MODE OF ADMINISTRATION

Not applicable.

CRITERIA FOR EVALUATION
Criteria for Evaluation – Safety
Safety was evaluated on the basis of AEs (reported and/or observed), changes in laboratory parameters, and vital signs. Clinically significant changes in laboratory parameters, vital signs and physical examination were recorded and evaluated as AEs.

Criteria for Evaluation – Efficacy
The primary efficacy parameter was the change from baseline in serum phosphorus levels. Change from baseline in levels of serum total, LDL, and HDL cholesterol and levels of serum calcium-phosphorus product were evaluated as secondary efficacy parameters. The percentage of responders at the end of study, defined as the percentage of patients reaching the serum phosphorous target range between 2.7 mg/dL and 4.6 mg/dL, inclusive, was also evaluated as a secondary efficacy parameter.

STATISTICAL METHODS

Safety:

All safety analyses were performed using the Safety Set. The Safety Set included all patients who received at least one dose of sevelamer carbonate.

All treatment emergent AEs and those related to sevelamer carbonate were summarized and tabulated for each MedDRA System Organ Class (SOC) and Preferred Term, both overall and by severity. For tabulations by severity, only a subject’s most severe event within the category (e.g. overall, SOC, or Preferred Term) was counted. Treatment emergent SAEs were also tabulated.

Vital signs (heart rate, respiratory rate, and systolic and diastolic blood pressure) at baseline and Day 56/ET, as well as the change from baseline to Day 56/ET, were summarized and assessed using Wilcoxon signed rank tests.

Data were summarized for laboratory evaluations performed at each study visit, along with the changes between screening and baseline, baseline and Day 56/ET, and Day 56 and Day 70. Changes were analyzed using Wilcoxon signed rank tests.

Efficacy:

The effects of treatment on serum phosphorus measurements, total cholesterol, LDL cholesterol, HDL cholesterol, and serum calcium (albumin adjusted)-phosphorus product were analyzed using the change from baseline to the end of the treatment period for Full Analysis Set (FAS). The FAS included the subset of the Safety Set with a baseline and at least one post-baseline serum phosphorus measure during treatment.

Descriptive statistics were calculated for serum phosphorus measurements at all study visits and for the changes between screening and baseline, baseline and Day 56/ET, and Day 56 to Day 70. A Wilcoxon signed rank test was used to assess the changes.

The proportion of patients attaining serum phosphorus response (serum phosphorus between 2.7 mg/dL and 4.6 mg/dL, inclusive) at each post baseline visit and for Day 56/ET were tabulated including number, percent, and 95% confidence intervals. The proportion of patients attaining serum phosphorus response according to KDOQI guidelines (serum phosphorus ≥ 2.7 and ≤ 4.6 mg/dL for Stage 4 patients and ≤ 5.5 mg/dL for Stage 5 patients) was also tabulated.

Descriptive statistics were calculated for serum total cholesterol, LDL cholesterol, HDL cholesterol, and serum calcium-phosphorus product at all study visits and for the changes between screening and baseline, baseline and Day 56/ET, and Day 56 to Day 70. A Wilcoxon signed rank test was used to assess the changes.

SUMMARY / CONCLUSIONS

Demographics and Renal History

Sixty-five percent of patients were male and 35% of patients were female, with a mean age of 62.0 years. Most patients were Caucasian (45 [92%]), with 1 Black patient (2%), 2 Asian patients (4%) and 1 patient (2%) listed as Other (Indian) comprising the rest of the population. The most common primary causes of chronic kidney disease were “other” (22%), diabetes (18%), glomerulonephritis (16%) and polycystic kidney disease (16%). Sixty-one percent of patients were taking a phosphate binder prior to entry. A total of 35% of the patients were classified as CKD stage 4 (GFR 15-29 mL/minute/1.73m²), with the remaining 65% of the patients being classified CKD stage 5 (GFR <15 mL/minute/1.73m²) not on dialysis according to Kidney Disease Outcomes Quality Initiative definitions.

Efficacy

The mean baseline serum phosphorus level was 6.2 mg/dL for the FAS. The corresponding mean level at Day 56/ET was 4.8 mg/dL. The decrease in serum phosphorus values from baseline to Day 56/ET was statistically significant (mean -1.4 mg/dL, p value < 0.001). The mean serum phosphorus increased to 6.5 ± 1.3 mg/dL following the post treatment washout period.

By the end of study treatment (Day 56/ET), 50% of patients in the FAS reached the titration target level of serum phosphorus ≥ 2.7 and ≤ 4.6 mg/dL following treatment with sevelamer carbonate. When examined by CKD stage using K-DOQI criteria, 75% of Stage 4 patients had reached the target level of a serum phosphorus ≥2.7 and ≤4.6 mg/dL and 70% of Stage 5 patients had achieved a serum phosphorus ≤ 5.5 mg/dL.

The mean serum calcium (albumin-adjusted)-phosphorus product at baseline was 53.07 mg²/dL² for the FAS. There was a statistically significant decrease in levels from baseline to Day 56/ET (mean 10.39 mg²/dL², p value < 0.001).

There was a statistically significant decrease in serum total and LDL cholesterol levels from baseline to Day 56/ET (-20% and -32% for total and LDL cholesterol, respectively; both p values < 0.001). There was no statistically or clinically significant change in serum HDL cholesterol or triglycerides.

Safety

The mean starting prescribed dose was 4.8 g/day, as specified by the protocol. The mean ending prescribed dose following the dose titrations during the study, was 7.8 g/day. The mean actual daily dose of sevelamer carbonate used in this study was 5.5 g/day (6-7 sevelamer carbonate 800 mg tablets per day) with a mean compliance of 89%.

In total, 137 treatment emergent AEs occurred in 44 patients (89.8%) during the study. The most frequently occurring AEs were coded to the MedDRA SOC Gastrointestinal Disorders (46.9%). Gastrointestinal Disorders occurring in >5% of patients included (by MedDRA Preferred Term): nausea (12 events in 11 [22.4%] patients), constipation (7 events in 6 [12.2%] patients), diarrhoea (8 events in 5 [10.2%] patients), vomiting (6 events in 5 [10.2%] patients) and flatulence (3 events in 3 [6.1%] patients). The majority of AEs were mild to moderate in intensity. Six (12.2%) patients experienced severe events, the majority of which occurred as single events in a single patient, except for lower respiratory tract infection (2 patients) and fluid overload (2 patients).

The most frequently occurring treatment related AEs coded to SOC Gastrointestinal Disorders (35 events in 16 [32.7%] patients). Gastrointestinal AEs assessed as related to sevelamer carbonate by investigators included: nausea (9 events in 8 [16.3%] patients), constipation (6 events in 5 [10.2%] patients), diarrhoea (6 events in 3 [6.1%] patients), and vomiting (4 events in 3 [6.1%] patients). All other treatment related AEs each occurred as a single event in a single patient. 

Eleven (22.4%) patients experienced 19 SAEs. No SAE was judged by the investigator to be related to sevelamer carbonate. The most frequent SAE by MedDRA Preferred Term was arteriovenous fistula operation (4 events in 4 (8.2%) patients). All 4 arteriovenous fistula operations involved the creation of, or surgery on a dialysis access.

One patient died during the course of this study. The patient, who discontinued the study due to an SAE of pleural effusion, died due to bronchopneumonia approximately 1 month after stopping sevelamer carbonate.

Statistically and clinically significant changes were seen in mean serum bicarbonate levels which increased by 1.3 mEq/L (from 16.2 to 18.2 mEq/L; p=0.005). There was also a statistically significant reduction in iPTH from baseline to Day 56/ET (-39 pg/mL, p = 0.013), an increase from 28.9 ±16.2 ng/mL at baseline to 31.1 ± 12.9 ng/mL at Day 56/ET (p = 0.080) in mean serum levels of 25-hydroxyvitamin D, and an increase from 8.5 ± 0.9 mg/dL at baseline to 8.8 ± 0.8 mg/dL at Day 56/ET (p<0.001) in mean serum calcium.

Mean values for all vital sign parameters were within the normal range. There were no clinically significant changes in vital signs overall or trends in vital signs changes over time.

Conclusion

The study demonstrated that sevelamer carbonate is both efficacious and well tolerated in hyperphosphatemic CKD patients not on dialysis, with a similar safety profile to that seen previously in sevelamer hydrochloride studies in hemodialysis patients. A statistically significant reduction in serum phosphorus was demonstrated in hyperphosphatemic CKD patients who were not on dialysis. Statistically significant reductions in levels of calcium (albumin-adjusted)-phosphorus product, total cholesterol and LDL cholesterol were also observed.