CLINICAL STUDIES
The ability of sevelamer to control serum phosphorus in CKD patients on
dialysis was predominantly determined from the effects of the hydrochloride
salt to bind phosphate. Six clinical trials used sevelamer hydrochloride
and three clinical trials used sevelamer carbonate. The sevelamer hydrochloride
studies include one double-blind, placebo-controlled 2-week study (sevelamer
N=24); two open-label, uncontrolled, 8-week studies (sevelamer N=220) and three
active-controlled open-label studies with treatment durations of 8 to 52 weeks
(sevelamer N=256). The sevelamer carbonate studies include one double-blind,
active-controlled, cross-over study with two 8-week treatment periods using
sevelamer carbonate tablets (N=79), one open-label, active-controlled,
cross-over study with two 4-week treatment periods using sevelamer carbonate
powder (N=31) and one randomized, parallel, open-label study using sevelamer
carbonate powder (N=144) dosed once daily or sevelamer hydrochloride tablets
(N=73) dosed three times daily for 24 weeks. Six of the active-controlled
studies are described here (three sevelamer carbonate and three sevelamer
hydrochloride studies).
Cross-Over Study of Sevelamer Carbonate (Renvela) 800 mg Tablets and Sevelamer Hydrochloride (Renagel) 800 mg Tablets ® ®
Stage 5 CKD patients on hemodialysis were entered into a
five-week sevelamer hydrochloride run-in period and 79 patients received,
in random order, sevelamer carbonate 800 mg tablets and sevelamer
hydrochloride 800 mg tablets for eight weeks each, with no intervening
washout. Study dose during the cross-over period was determined based on
the sevelamer hydrochloride dose during the run-in period on a gram per
gram basis. The phosphorus levels at the end of each of the two
cross-over periods were similar. Average actual daily dose was 6 g/day
divided among meals for both treatments. Thirty-nine of those completing
the cross-over portion of the study were entered into a two-week washout
period during which patients were instructed not to take any phosphate
binders; this confirmed the activity of sevelamer in this
study.
Cross-Over Study of Sevelamer Carbonate (Renvela) Powder and Sevelamer Hydrochloride (Renagel) Tablets ® ®
Stage 5 CKD patients on hemodialysis were entered into a
four-week sevelamer hydrochloride run-in period and 31 patients received,
in random order, sevelamer carbonate powder and sevelamer hydrochloride
tablets for four weeks each with no intervening washout. Study dose
during the cross-over period was determined based on the sevelamer
hydrochloride dose during the run-in period on a gram per gram basis. The phosphorus levels at the end of each of the two cross-over periods
were similar. Average actual daily dose was 6.0 g/day divided among
meals for sevelamer carbonate powder and 6.4 g/day divided among meals
for sevelamer hydrochloride tablets.
Sevelamer Hydrochloride Versus Active-Control, Cross-Over Study in Hemodialysis Patients
Eighty-four CKD patients on hemodialysis who were
hyperphosphatemic (serum phosphorus > 6.0 mg/dL) following a
two-week phosphate binder washout period were randomized in a cross-over
design to receive in random order sevelamer hydrochloride and
active-control for eight weeks each. Treatment periods were separated by
a two-week phosphate binder washout period. Patients started on treatment
three times per day with meals. Over each eight-week treatment period, at
three separate time points the dose of sevelamer hydrochloride could be
titrated up to control serum phosphorus, the dose of active-control could
also be altered to attain phosphorus control. Both treatments
significantly decreased mean serum phosphorus by about 2 mg/dL ().
Table 4
Table 4. Mean Serum Phosphorus (mg/dL) at Baseline and Endpoint
|
Sevelamer
Hydrochloride (N=81)
|
Active Control (N=83)
|
Baseline
at End of Washout |
8.4 |
8.0 |
Endpoint |
6.4 |
5.9 |
Change
from Baseline at Endpoint (95% Confidence Interval)
|
-2.0
(-2.5, -1.5)
|
-2.1
(-2.6, -1.7)
|
The distribution of responses is shown in. The
distributions are similar for sevelamer hydrochloride and active control.
The median response is a reduction of about 2 mg/dL in both groups. About
50% of subjects have reductions between 1 and 3 mg/dL.
Figure 2
Figure 2. Percentage of patients
(Y-axis) attaining a phosphorus reduction from baseline (mg/dL) at
least as great as the value of the X-axis.
Average daily sevelamer hydrochloride dose at the end of
treatment was 4.9 g (range of 0.0 to 12.6 g).
Sevelamer Hydrochloride Versus Active-Control in Hemodialysis Patients
Two hundred CKD patients on hemodialysis who were
hyperphosphatemic (serum phosphorus > 5.5 mg/dL) following a
two-week phosphate binder washout period were randomized to receive
sevelamer hydrochloride 800 mg tablets (N=99) or an active-control
(N=101). At week 52, using last-observation-carried-forward, sevelamer
and active-control both significantly decreased mean serum phosphorus
().
Table
5
Table 5. Mean Serum Phosphorus (mg/dL) and Ion Product at
Baseline and Change from Baseline to End of Treatment
|
Sevelamer HCl (N=94)
|
Active-Control (N=98)
|
Phosphorus Baseline Change from Baseline at Endpoint
|
7.5 -2.1
|
7.3 -1.8
|
Ca x Phosphorus Ion Product Baseline Change
from Baseline at Endpoint
|
70.5 -19.4
|
68.4 -14.2
|
Sixty-one percent of sevelamer hydrochloride patients and 73% of
the control patients completed the full 52 weeks of treatment.
, a plot of the phosphorus
change from baseline for the completers, illustrates the durability of
response for patients who are able to remain on treatment.
Figure 3
Figure 3. Mean Phosphorus Change from
Baseline for Patients who Completed 52 Weeks of Treatment
Average daily sevelamer hydrochloride dose at the end of
treatment was 6.5 g (range of 0.8 to 13 g).
Sevelamer Hydrochloride Versus Active-Control in Peritoneal Dialysis Patients
One hundred and forty-three patients on peritoneal dialysis who
were hyperphosphatemic (serum phosphorus > 5.5 mg/dL) following a
two-week phosphate binder washout period were randomized to receive
sevelamer hydrochloride (N=97) or active-control (N=46) open label for 12
weeks. Average daily sevelamer hydrochloride dose at the end of treatment
was 5.9 g (range 0.8 to 14.3 g). Thirteen patients (14%) in the sevelamer
group and 9 patients (20%) in the active-control group discontinued,
mostly for gastrointestinal adverse reactions. There were statistically
significant changes in serum phosphorus (p<0.001) for sevelamer
hydrochloride (-1.6 mg/dL from baseline of 7.5 mg/dL), similar to the
active-control.
Once a Day Versus Three Times a Day Dosing
Stage 5 CKD patients on hemodialysis with a serum phosphate
level of > 5.5 mg/dL after washout from baseline therapies were
randomized in a 2:1 ratio to receive either sevelamer carbonate powder
once-daily (N=144) or sevelamer hydrochloride as a tablet with the dose
divided three times per day (N=73) for 24 weeks. The initial dose for the
two groups was 4.8 g/day. At the end of the study, the total daily dose
was 6.2 g/day of sevelamer carbonate powder once daily and 6.7 g/day of
sevelamer hydrochloride tablets three times per day. A greater percentage
of subjects on the once daily dose than three times per day regimen
discontinued therapy prematurely, 35% versus 15%. The reasons for
discontinuation were largely driven by adverse events and withdrawal of
consent in the once daily dosing regimen. Serum phosphate levels and
calcium-phosphate product were better controlled on the three times per
day regimen than on the once daily regimen. Mean serum phosphorus
decreased 2.0 mg/dL for sevelamer carbonate powder once daily and 2.9
mg/dL for sevelamer hydrochloride tablets three times per day.
|