Protocol GTC-68-209: A Randomized, Cross-Over Study to Compare Once a Day Sevelamer Dosing with Three Times per Day Sevelamer Dosing

Renagel^® (sevelamer hydrochloride)

Drug Name	Generic Name	Studied Indications or Disease	Approved U.S. Drug Label
Renagel®	sevelamer hydrochloride	chronic kidney disease	Prescribing Info

Name of Sponsor/Company

Genzyme Corporation, 500 Kendall Street, Cambridge, MA 02142
Geltex Pharmaceuticals, Inc., Waltham, MA 02451, (Geltex Pharmaceuticals, Inc. was acquired by Genzyme Corporation December 2000)

Investigators and Study Center(s)

This study took place at 2 sites in the United States.

Publication (Reference)

Publications

Studied Period

First patient entered: 21 August 2003
Last patient completed: 6 May 2004

Phase of Development

Phase 2

Objectives

The primary objectives were:

To evaluate the equivalency of once per day dosing of sevelamer, given with the largest meal, to standard three times per day dosing of sevelamer, on serum phosphorus control in hemodialysis patients.

To evaluate the safety and tolerability of once per day dosing with sevelamer, given with the largest meal, in hemodialysis patients.

The secondary objective was:

To evaluate the equivalency of once per day dosing of sevelamer, given with the largest meal, to standard three times per day dosing of sevelamer on the following laboratory parameters: serum calcium corrected for albumin, calcium-phosphorus product, albumin, intact parathyroid hormone, total, LDL, HDL, and non-HDL cholesterol, and triglycerides.

Methodology

This was a phase 2, randomized, cross-over, open-label study conducted at two centers within the United States. The study consisted of a screening period, a two-week sevelamer three times per day run-in period, and 2 four-week treatment periods. During the treatment period, patients were randomly assigned to one of two treatment sequences: sevelamer dosed once per day with the largest meal followed by standard three times per day dosing or sevelamer dosed three times per day followed by sevelamer dosed once per day with the largest meal.

Number of Patients (Planned and Analyzed)

No. Enrolled, Randomized, and Treated:24/21
No. Completed:18

Diagnosis and Main Criteria for Inclusion

Patients included in the study were adult males or females on a stable three-times weekly hemodialysis regimen and on a stable dose of Renagel^®.

Test Product, Dose, and Mode of Administration

Sevelamer hydrochloride (Renagel^®): 400 mg tablets
Sevelamer hydrochloride (Renagel^®): 800 mg tablets

The starting dose was individualized for each patient based on the prescribed daily dose prior to screening and patients continued the same daily dose throughout the study.

Administered orally once per day with the largest meal.

Duration of Treatment

The total study duration was 10 weeks. This included a two-week sevelamer three times per day Run-In period and two four-week randomized treatment periods.

Reference Therapy, Dose and Mode of Administration

Sevelamer hydrochloride (Renagel^®): 400 mg tablets
Sevelamer hydrochloride (Renagel^®): 800 mg tablets

The starting dose was individualized for each patient based on the prescribed daily dose prior to screening and patients continued the same daily dose throughout the study

Administered orally three times per day with meals.

CRITERIA FOR EVALUATION
Efficacy

The treatment regimens were compared on the basis of serum phosphorus at the end of each treatment period, averaging the phosphorus values from the last two weeks of each treatment period. The treatment regimens were also compared on the basis of calcium corrected for albumin, calcium-phosphorus product, albumin, iPTH, total, LDL, HDL, and non-HDL cholesterol, and triglycerides, averaging the laboratory values for each parameter from the last two weeks of each treatment period (total of 4 measures per treatment period).

Safety

Safety was evaluated on the basis of adverse experiences and changes in laboratory values.

STATISTICAL METHODS
Efficacy

The primary efficacy measure was based on a comparison of serum phosphorus control observed in each treatment regimen performed on the Completer Population (all patients who completed both sevelamer treatment periods) as is standard for equivalence testing. The effects of once per day dosing and standard three times per day dosing on the control of serum phosphorus were determined using equivalence testing. The mean of the measurements from the last two weeks in each treatment period were used for the purposes of analysis. These means were calculated using the area under the curve (AUC) based on the trapezoidal rule to obtain a time-weighted mean because this methodology can accommodate the varying number of assessments that could arise in the two weeks (between 1 and 4 measurements) and the varying intervals between assessments. Equivalence was assessed based on a 5% Two One-Sided Test (TOST) equivalence test of the ratio of the revised to standard mean AUC on the log-transformed scale. This test required that a 90% confidence interval for the ratio, after back-transformation to the original scale, was within the interval (0.80, 1.25).

The secondary efficacy measure was based on a comparison of the laboratory levels for calcium corrected for albumin, calcium-phosphorus product, albumin, iPTH, total, LDL, HDL and non-HDL cholesterol, and triglyceride levels. The effects of once a day dosing and standard three times per day dosing on these laboratory levels were determined using equivalence testing in the same manner specified for serum phosphorus.

Safety

Safety was evaluated on the basis of adverse events and changes in safety laboratories and included all patients who received study treatment. Adverse events were summarized overall, by MedDRA system organ class, and by MedDRA preferred term for each treatment regimen. The number and percentage of patients with treatment emergent adverse events (defined as adverse events that occurred for the first time on or after the date of randomization; or, first occurred prior to the date of randomization and worsened in severity during the randomization period) were tabulated by system organ class, and by MedDRA preferred term for each dosing regimen overall, and by treatment sequence. Treatment emergent adverse events possibly or probably related to study medication were tabulated in the same manner. Treatment emergent adverse events were also summarized by maximum intensity.

SUMMARY – CONCLUSIONS
Demographics and Renal History

The mean age of the patients was 64 years. Sixty-two percent of the patients were male and 38% were female. Most patients were Black (57%) with Caucasians comprising the remaining 43% of the population. The three most common primary causes of chronic renal failure were hypertension (38%), diabetes (33%) and glomerulonephritis (14%).

Efficacy

Once per day dosing (QD) of sevelamer with the largest meal was found to be as effective as three times per day (TID) dosing with meal in controlling serum phosphorus, calcium, calcium x phosphorus product, albumin, and serum lipids. Bioequivalence was not demonstrated for iPTH. This study was not powered for this due to high variability of iPTH values.

Bioequivalence Analysis.

Laboratory Parameter	TID (Mean† ± SE)	QD (Mean† ± SE)	90% CI
Phosphorus (mg/dL)	4.6 ± 0.3	5.0 ± 0.3	0.83, 1.01*
Calcium (mg/dL) Calcium – Phosphorus Product mg2/dL3	9.5 ± 0.2 44.0 ± 2.8	9.4 ± 0.2 47.3 ± 2.7	0.99, 1.03* 0.84, 1.03*
Albumin (gm/dL) Ipth (pg/mL)	3.8 ± 0.1 216.8 ±38.2	3.8 ± 0.1 247.0 ± 40.8	0.99, 1.01* 0.75, 1.02
Total Cholesterol (mg/dL) LDL Cholesterol (mg/dL)	132.5 ± 7.7 58.1 ± 6.0	135.0 ± 7.8 60.5 ± 5.4	0.95, 1.01* 0.89, 1.04*
HDL Cholesterol (mg/dL) Non-HDL Cholesterol (mg/dL)	39.2 ± 2.4 90.4 ± 7.8	39.8 ± 2.4 92.5 ± 7.8	0.95, 1.03* 0.91, 1.04*
Triglycerides (mg/dL)	148.4 ± 22.1	144.3 ± 24.0	0.94, 1.12*

*90% CI for the ration is within the interval (0.8, 1.25)
^†Time Weighted Mean

Safety Results

The average daily dose of sevelamer was 6.7 g. No patients changed their sevelamer daily dose from one treatment regimen to the other. During the TID treatment phase, only one patient deviated from TID dosing and took the daily dose two times per day throughout the treatment phase. Overall, treatment compliance was slightly higher for the QD dosing regimen (97% vs. 92% for the QD and TID treatments, respectively), but this difference was not statistically significant, p = 0.1115.

Overall, both three times per day and one time per day sevelamer dosing were well tolerated during this study. There were 21 patients evaluated in the Safety Population. During the randomized treatment period, nine (43%) patients reported an adverse event (AE) during the TID regimen and 12 (57%) reported an adverse event during the QD regimen. The majority of the treatment emergent adverse events reported were mild to moderate in intensity. The system organ classes with the most frequently reported adverse events were: gastrointestinal disorders; infections and infestations; injury, poisoning and procedural complications; and, metabolism and nutrition disorders. Four (19%) patients reported treatment-emergent adverse events classified as possibly or probably related to sevelamer treatment during the QD treatment sequence. All four treatment related adverse events (constipation, flatulence, hyperphosphatemia, and hypophosphatemia) were mild in nature. No treatment related adverse events were reported during the TID treatment period.

Two patients died during the study; both deaths were classified as not related to the study medication by the Investigator. Three (14%) patients in the TID treatment regimen and 4 (19%) in the QD treatment regimen had serious adverse events. None were determined to be related to study medication by the investigator. One (5%) patient withdrew due to an adverse event (cerebrovascular accident) while prescribed sevelamer TID and 2 (10%) patients withdrew due to an adverse event (cardiac arrest, hypophosphatemia) while prescribed sevelamer QD. Of these, one adverse event (hypophosphatemia) was classified as possibly related to study medication by the Investigator.

Routine laboratory measures were similar between the treatment regimens. There were no clinically significant changes in the laboratory parameters examined. Furthermore, there were no clinically significant findings in vital signs or physical exam abnormalities.

Conclusion

The results of this study suggest that once per day sevelamer dosing with the largest meal is safe and effective in hemodialysis patients previously receiving sevelamer three times per day.