RD patients on hemodialysis who were hyperphosphatemic (serum phosphorus >5.5 mg/dL but <7.75 mg/dL) following a 2-week phosphate binder washout period, were randomized to receive Velphoro at 250 mg/day, 1,000 mg/day, 1,500 mg/day, 2,000 mg/day, or 2,500 mg/day or active-control (sevelamer hydrochloride). Velphoro treatment was divided across meals, depending on dose. No dose titration was allowed. Within each of the groups, the serum phosphorus level at the end of treatment was compared to baseline value. Velphoro was shown to be efficacious (p≤0.016) for all doses except 250 mg/day. There were no patient-reported dose limiting treatment-emergent adverse events.
Mean changes in iron parameters (ferritin, transferrin saturation (TSAT) and transferrin) and vitamins (A, D, E and K) were generally not clinically meaningful and showed no apparent trends across the treatment groups. Velphoro had a similar GI adverse event profile [see Adverse Reactions (6.1)] to sevelamer hydrochloride, and no dose-dependent trend in GI events was observed.
14.2 Dose Titration Study
In Study-05A, 1,054 patients on hemodialysis (N=968) or peritoneal dialysis (N=87) with serum phosphorus ≥6 mg/dL following a 2-4 week phosphate binder washout period, were randomized and treated with either Velphoro, at a starting dose of 1,000 mg/day (N=707), or active-control (sevelamer carbonate, N=348) for 24 weeks. At the end of Week 24, 93 patients on hemodialysis whose serum phosphorus levels were controlled (<5.5 mg/dL) with Velphoro in the first part of the study, were re-randomized to continue treatment with either their Week 24 maintenance dose (N=44 or a non-effective low dose control 250 mg/day, N=49) of Velphoro for a further 3 weeks. At Week 27, a superiority analysis of the Velphoro maintenance dose versus low dose was performed. The maximum dose of Velphoro was 3,000 mg/day (6 tablets/day) and the minimum dose was 1,000 mg/day (2 tablets/day). Velphoro was administered with food and the daily dose was divided across the largest meals of the day.
The Velphoro maintenance dose (1,000 to 3,000 mg/day) was statistically significantly superior in sustaining the phosphorus lowering effect in hemodialysis patients at Week 27 (p<0.001) compared with the non-effective low dose control. The results are provided in TABLE 2.
Table 2 Mean (SD) Serum Phosphorus and Change from Baseline to End of Treatment
* p<0.001 for the difference in least square means of the change from BL to Week 27/End of Treatment (LOCF principle) between Velphoro maintenance dose and low dose using a covariance analysis (MIXED Model).
Notes: BL is Week 24 or latest value available before Week 24 when Week 24 result is missing; End of Treatment is Week 27 value or includes the latest eva luable measurement after Week 24 (i.e., LOCF). BL = Baseline; LOCF = Last observation carried forward; SD = Standard deviation.
Mean (SD) Serum Phosphorus (mg/dL)
Velphoro Maintenance Dose
(1,000 to 3,000 mg/day)
(N=44) Velphoro Low Dose Control
(250 mg/day)
(N=49)
Week 24 (BL) 4.7 (1.03) 5.0 (1.14)
Week 25 4.7 (0.91) 6.3 (1.44)
Week 26 4.7 (1.21) 6.6 (1.91)
Week 27/End of
Treatment 5.0 (1.07) 6.8 (1.63)
Change from BL to End of
Treatment 0.3 (1.22)* 1.8 (1.47)
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