Protocol BCI-CH-114-LA: A Multicenter, Open-label Study of the Efficacy and Safety of Intravenous 1α-Hydroxyvitamin D₂ in Reducing Elevated Blood Parathyroid Hormone Levels in End Stage Renal Disease Patients on Hemodialysis

Hectorol® (doxercalciferol)

Drug Name	Generic Name	Therapeutic Area and FDA Approved Indications:	Approved U.S. Drug Label
Hectorol®	doxercalciferol injection	Therapeutic Area: Chronic Kidney Disease FDA Approved Indications - Injection: Hectorol® is indicated for the treatment of secondary hyperparathyroidism in patients with chronic kidney disease on dialysis.	Prescribing Info for Hectorol® Injections

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

PUBLICATION (REFERENCE)

Publications

NAME OF SPONSOR/COMPANY:

Genzyme Corporation, 500 Kendall Street, Cambridge, MA 02142
Bone Care International, Inc., Middleton, WI 53652 (Bone Care was acquired by Genzyme Corporation July 2005)

TITLE OF STUDY:

Protocol BCI-CH-114-Memphis: A Multicenter, Open-label Study of the Efficacy and Safety of Intravenous 1α-Hydroxyvitamin D₂ in Reducing Elevated Blood Parathyroid Hormone Levels in End Stage Renal Disease Patients on Hemodialysis

INVESTIGATORS AND STUDY CENTER(S):

This was a multicenter study conducted at eleven locations in the United States.

STUDIED PERIOD:

First patient enrolled: 02 July 1997
Last patient completed: 11 February 1998

PHASE OF DEVELOPMENT:

Phase 3

OBJECTIVES:

To establish the safety and efficacy of pulse dose intravenous Hectorol® as a therapy for secondary hyperparathyroidism in patients with Chronic Kidney Disease Stage 5 on hemodialysis.

METHODOLOGY:

This study was a Phase 3, multicenter, open-label, 12-week treatment, crossover extension of Protocol BCI-CH-108-LA (A Multicenter, Double-Blind, Placebo-Controlled Study of the Efficacy and Safety of Oral 1α-Hydroxyvitamin D₂ in Reducing Elevated Blood Parathyroid Hormone Levels in End Stage Renal Disease Patients on Hemodialysis). The study consisted of an 8-week Washout Period followed by a 12-week Hectorol Treatment Period.

Patients had hemodialysis 3 times per week and laboratory measurements at regular intervals.

If patients experienced hypercalcemia (serum calcium > 11.2 mg/dL) or hyperphosphatemia (serum phosphorus > 8.0 mg/dL), Hectorol was stopped until the serum calcium or phosphorus was lowered and then resumed at a lower dose. In patients with mild hypercalcemia (serum calcium of >10.5 to 11.2 mg/dL) or moderate hyperphosphatemia (serum phosphorus of 7.0 to 8.0 mg/dL) the calcium-based phosphate binder and/or study drug was reduced. If the plasma iPTH was less than 150 pg/mL, the study drug was stopped and resumed at a lower dose the following week.

NUMBER OF PATIENTS (PLANNED AND ANALYZED):

No. Enrolled: 40
No. Treated: 28
No. Completed: 26

DIAGNOSIS AND MAIN CRITERIA FOR INCLUSION:

Patients who participated in Protocol BCI-CH-108-LA were eligible for enrollment into the Washout Period. Patients were male or female, between the ages of 20 to 75 years, who had been on hemodialysis three times a week for at least four months, with a history of elevated iPTH values (> 400 pg/mL).

TEST PRODUCT, DOSE, AND MODE OF ADMINISTRATION:

Hectorol: 2 mcg/mL intravenous solution
The initial dose was 4 mcg after each hemodialysis session (12 mcg/week).
Doses were given intravenously three times per week.

DURATION OF TREATMENT:

8-week Washout Period followed by 12-week Treatment Period.

REFERENCE THERAPY, DOSE AND MODE OF ADMINISTRATION:

Not applicable

CRITERIA FOR EVALUATION:

Criteria for Evaluation - Efficacy:
Plasma iPTH was evaluated for evidence of the test drug’s efficacy; bone-specific serum markers were also monitored at selected intervals.

Criteria for Evaluation - Safety:
Safety was evaluated based on adverse events, serum calcium, and serum phosphorus, as well as hematology laboratory parameters and other chemistry parameters.

STATISTICAL METHODS:
Comparisons were considered to be statistically significant if the two-sided p-value was ≤ 0.05. Missing values were imputed using last observation carried forward.

Statistical Methods - Efficacy:
Baseline values for plasma iPTH, calcium, and phosphorus were defined as the average of the data collected during the last three visits of the Washout Period.

At each post-baseline determination, as well as the last visit for each subject, the significance of the change from baseline for each of the evaluable parameters was determined using a paired t-test.

Statistical Methods – Safety:
All adverse events were recorded.

At each post-baseline determination as well as at the last visit for each subject, the significance of the change from baseline for calcium and phosphorus was determined using a paired t-test.

SUMMARY / CONCLUSIONS

Summary / Conclusions - Demographics:
The 28 patients enrolled in the treatment period were aged between 23 and 73 years (mean = 54 years) and had been on hemodialysis for at least 4 months (mean = 65 months). Fourteen patients were male and fourteen were female. Seventeen patients were African-American; seven were Caucasian, and four were Hispanic.

Summary / Conclusions – Efficacy:
Both intent-to-treat (ITT; N=28) and per protocol (PP; N=24) analyses were performed. The results presented below are from the per protocol analyses, unless otherwise noted.

Parathyroid Hormone (PTH): At baseline, mean plasma iPTH was 705.4 pg/mL. After treatment was initiated, mean iPTH decreased to 404.5 pg/mL by the end of the study (p < 0.001). All 24 patients (100.0%) achieved iPTH suppression of ≥ 30% on or before Week 8 of the study. The average dose of Hectorol required to achieve ≥ 30% iPTH suppression was 3.8 mcg per hemodialysis session. By the end of the study, plasma iPTH was reduced to 56.2% of the baseline value (p < 0.00l). Eighteen (75.0%) of the 24 patients reached the pre-determined target iPTH range of l50 to 300 pg/mL during treatment with Hectorol.

Osteocalcin: There was a trend toward an increase in mean serum osteocalcin over time with intravenous Hectorol treatment; however, this trend did not reach statistical significance. Baseline mean osteocalcin was 7l.8 ng/mL compared to 77.0 ng/mL at the end of the study.

Bone-Specific Alkaline Phosphatase (BSAP): A statistically significant decrease of 24.6% in mean BSAP was observed at the end of the study, with a mean of 36.6 U/L at Week l2 compared to a mean of 48.7 U/L at baseline (p ≤ 0.00l).

Summary / Conclusions – Safety Results:
Adverse Events: There were no non-serious adverse events with possible or unknown causality to study drug. Eleven treatment emergent serious adverse events occurred in eight patients during the 12-week doxercalciferol Treatment Period. No patients died during the 12-week doxercalciferol Treatment Period. All serious adverse events were assessed as not related to study drug by the investigator.

Three episodes of hypercalcemia (defined as serum calcium above 11.2 mg/dL) occurred in three patients during treatment with doxercalciferol. Eight episodes of hyperphosphatemia (defined as serum phosphorus above 8.0 mg/dL) occurred in four patients during treatment with doxercalciferol.

Serum Calcium: A mean increase of 0.80 mg/dL in serum calcium from baseline was observed during the 12- week doxercalciferol Treatment Period; this increase was statistically significant (p < 0.001) but well within the normal range (8.4 - 10.2 mg/dL).

Serum Phosphorus: Mean serum phosphorus remained unchanged after 12 weeks on intravenous doxercalciferol therapy.

Clinical Chemistry, Hematology, Vital Signs: A significant decrease in serum total alkaline phosphatase was observed after 8 weeks of treatment with intravenous doxercalciferol which continued through Week l2. No other clinically meaningful changes in clinical chemistry, hematology, or vital signs were observed.

CONCLUSION:

Hectorol (doxercalciferol injection) is safe and effective in treating secondary hyperparathyroidism associated with Stage 5 Chronic Kidney Disease.

Based on report prepared on: 16 January 2002
Synopsis prepared on: 10 November 2006