iiiNICAL REVIEW
`
`Clinical Review Section
`
`receive the nextbottle number(s). The site personnel were asked for subject information that
`included central laboratory iPTH and serum calcium values and safety information.
`
`If any of the following criteria applied, a subject’s dose was NOT increased:
`
`‘ForweeksS, 6, 9and 12:
`o The mean of the 2 central laboratory iPTH values from the preceding 2 weeks was < 200
`pg/mL (21.2 p'mol/L), with any missing values excluded fi'om calculation.
`
`For weeks 16, 20, and 24:
`
`o The central laboratory iPTH value from the preceding study visit was 5 200 pg/mL (21.2
`pmol/L) with any missing value replaced by the most recent past value.
`
`For weeks 3, 6, 9, 12, 16, 20, and 24:
`o The highest dose of study medication was reached.
`0 The serum calcium was < 7. 8 mg/dL (1.95 mmol/L) or the subject was experiencing
`symptoms of hypocalcemia.
`.
`0 The subject was experiencing an adverse event that precluded a doseincrease.
`
`If iPTH values were < 100 pg/mL (10.6 pmol/L) for 3 consecutive study visits, study
`medication was reduced to the next lower dose. If the subject was already receiving the
`lowest dose of study drug, vitamin D therapy could be decreased.
`
`Treatment of HEocalcemia: If a subject experienced symptoms of hypocalcemia and/or a serum
`calcium < 8.4 mg/dL, calcium supplements and/or phosphate binders may have been increased to
`resolve these Symptoms (if present) or to increase serum calcium to 2 8.4 mg/dL. If these
`measures were insufficient, the vitamin D dose could be increased. Guidelines used for
`_ management of hypocalcemia are outlined in the figure below:
`
`Smudm<8AmoI¢anor
`Worn-(aim ~
`
`MMWGWflWWmWMMMMNM.
`
`wmmevsmmm
`“WW
`Wmmmoam
`
`WMGM ..__.__..’
`
`8ame-Ic5m1hwwtok80nvgldu
`
`-nmwmmmmuamdmmfimmgmcamxme
`
`Roan-miniaydnmal
`WWW
`
`Protocol Specified Guidelines for Changes in Vitamin D therapy: If a subject’s iPTH
`concentration increased 2 50% from baseline for 3 consecutive study visits, vitamin D therapy
`
`Page 95
`
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`

`
`
`V Clinical Review Section
`
`was increased. If a subject’s serum calcium concentration was > 11 mg/dL (2.75 mmol/L), or
`serum phosphorus concentration Was > 6.5 mg/dL (2.1 mmol/L), and/or Ca x P was > 70
`(mg/dL)2 (5.65 [mmol/L])2, the investigator could modify diet and/or change dose or brand of
`phosphate binders. If these measures were not sufficient, vitamin D could be withheld or the
`- dose reduced until the serum calcium, phosphorus, and Ca x P were below these levels. If
`vitamin D sterol was withheld, it was restarted at the investigator’s discretion.
`
`Withdrawal criteria: Any subject had the right to withdraw from the study at any time and for
`any reason. Subjects could be withdrawn from the study in the event of kidney transplant,
`parathyroidectomy or pregnancy. Withdrawn patients were not replaced.
`
`~ Statistical Analyses: It was hypothesized that the results of this study would demonstrate the
`following:
`
`0 Cinacalcet decreases mean iPTH concentrations to S 250 pg/mL in a significantly greater
`proportion of subjects with ESRD and secondary HPT compared with placebo.
`o Cinacalcet reduces mean iPTH concentrations by_> 30%1n a significantly greater
`proportion of subjects compared with placebo.
`o Cinacalcet causes a significantly greater mean percentage reduction in Ca x P compared
`with placebo.
`o Cinacalcet significantly1mproves cognitive functioning compared with placebo.
`
`The sample size calculation was based on a x2 test of equal proportions of subjects with a mean
`iPTH value 5 250 pg/mL during the efficacy—assessment phase, with a statistical significance
`level of 0.05 (2-sided). The placebo response was predicted on the basis of previous cinacalcet
`phase 2 studies to be < 15%. With a cinacalcet response rate of 35% assumed for the purpose of
`sample size considerations, the planned 320 subjects (160 cinacalcet, 160 placebo) yielded 95%
`power.
`,
`
`A 4-stage hypothesis testing procedure was performed for the primary and secondary endpoints.
`The primary endpoint was tested at a significance level of 0.05. The firSt secondary endpoint,
`the proportion of subjects with a reduction from baseline in mean iPTH 2 30% during the
`efiicacy—assessment'phase, was to be tested only ifstatistical significance was achieved for the
`primary endpoint. The key secondary endpoint, percentage change from baseline in mean Ca x
`P, was to be tested only if statistical significance was achieved for the first secondary endpoint.
`Similarly, the final secondary endpoint, the change from baseline in PRO cognitive functioning
`scale score, was to be tested only if statistical significance was achieved for the key secondary
`endpoint.
`'
`
`Descriptive statistics were used to summarize each efficacy endpoint at each measurement time
`point during the dose-titration and efficacy-assessment phases. Descriptive statistics included
`i mean, median, SE, 25th and 75th percentiles, minimum, and maximumfor continuous variables
`and number and percent for categorical variables. For continuous efficacy variables, 95% 2-
`sided confidence intervals (CIs) were provided for the means. For categorical efficacy variables,
`
`Page 96
`
`

`

`
`
`Clinical Review-Section
`
`the odds” ratio of achieving the endpoint under consideration and the difference between the
`treatment groups were presented with the associated 95% C15.
`
`The statistical analysis plan was amended once (22 April 2003). The amendment included the
`following changes:
`‘
`
`o
`
`o
`0
`
`3
`
`redefinition of the primary iPTH dataset and addition of sensitivity analyses for iPTH-
`. related endpoints afier identification of inconsistenciesin the acceptability criteria for
`iPTH assays at \ L--—~———_—~__./:l and affiliates
`inclusion of analyses of ECG interval data
`clarification regarding analyses if subjects had been randomized to an incorrect iPTH and
`Ca x P stratum
`’
`
`Protocol Amendments: The protocol was amended once changes noted below:
`0 Changed the tertiary endpoint, proportion of subjects with a reduction from baseline in
`mean iPTH of 2 30%, to a secondary endpoint
`o The eligibility criteria were clarified to allow women with a defmite history of -
`amenorrhea to enroll in the study if the pregnancy test falsely reported as positive -
`
`Results
`
`Patient Disposition: As shown in the table below, 498 subjects were screened and 331 subjects
`were enrolled and randomized this study. Approximately 80% of placebo and 64% of cinacalcet
`subjects completed the 26 week trial. Adverse events were the most common reason for early
`withdrawal, with the rate higher in the cinacalcet-treated group (23%) compared with the
`placebo-treated group (5%).
`
`'
`
`38 (23) Deaths
`
`Enrolled
`No treatment
`At least one dose
`
`Withdrew - Total
`Withdrew - AB
`
`‘
`
`.
`
`'
`
`Withdrew - Parathyroidectomy
`Withdrew - Renal Transplant
`Withdrew - Other
`Completed Titration Phase (Weeks 1-16)
`Com -leted Stud
`
`-
`
`165
`0
`165
`
`33 (20)
`9 (5)
`5(3)
`3 (2)
`9 (5)
`7 (4)
`151 (92)
`
`r
`
`,
`
`.
`
`'
`
`166
`1
`165
`
`.
`
`58 (35)
`
`-
`
`.
`
`3 (2) -
`O (0)
`8 (5)
`9 (5)
`136 (82)
`
`-
`
`Protocol Violations: Twenty one (6%) subjects had eligibility deviations in this study, which
`were discovered after subjects were enrolled. The most common eligibility deviation was a
`change in vitamin D sterol dose during the 30 days before day 1. Major protocol deviations
`occurred in 51% of the placebo-treated subjects and 57% of the cinacalcet-treatedsubjects (see
`table below). Compliance with study drug was 91% in the cinacalcet treated group and 94% in'
`the placebo treated group.
`
`Page 97
`
`

`

`
`
`Stud 20000183
`imsoOtoSOOandCaxP 7o
`
`-
`
`
`
`
`
`_
`
`
`
`
`
`
`.
`
`iPTH>800 andCaxP 7o
`iPTH>800andCaxP>70
`
`,
`
`
`
`1y;2_(_59%)
`6/10 60%
`
`
`
`
`
`14/23 61%
`7/10 70%
`
`
`
`COMMENTS: Although there were numerous and varied protocol violations, the numbers
`and types of violations were fairly evenly distributed across the groups. It is unlikely that
`the protocol violations affected the principal efficacy or safety results.
`
`Demographics: Baseline subject demographics were well balanced across the treatment groups
`(see table below). Ninety-two percent of enrolled subjects were white and 63% were male.
`_
`Approximately 33% of enrolled subjects were 2 65 years of age. The duration of dialysis ranged
`from 3 to 358 months, with a mean of 81 months. Randomization within each baseline stratum
`was balanced between treatment groups. At baseline, mean iPTH, Ca x P, serum calcium, and
`serum phosphorus were similar in the einacalcet and placebo groups. At study entty, vitamin D
`and phosphate binder use were similar in the 2 treatment groups.
`~
`#94”
`I
`b‘
`Placebo
`165 %
`56.3 :h 15.0
`
`.
`N
`
`.
`
`i
`
`-.
`
`i
`
`H fl
`
`Cinacalcet
`166 %
`55.2 i 14.8
`
`'
`
`Yes
`
`- Z 65 years
`275 years
`Sex
`
`.
`
`»
`
`Male
`Female
`Race
`Caucasian
`Black
`-
`Other
`Randomization Strata
`
`'
`
`.
`
`,
`
`,
`
`PTH 300 - 500, Ca x P S 70
`PTH 300 — 500, Ca x P > 70
`PTH 500 — 800, Ca x P S 70
`PTHSOO—800,CaxP>70
`’ PTH>800,CaxPS70
`PTH >800, Ca x P > 70
`Baseline Labs
`
`_
`
`'
`
`iP’I‘H (pg/mL)
`Serum Ca (mg/dL)
`CaxP(mg/dL)2
`Serum Phos (mg/dL)
`Baseline Vitamin D use
`
`.
`
`56 (34)
`‘. 19(12)
`
`107 (65)
`58 (35)
`
`157 (95)
`2 (l)
`6 (4)
`
`'
`
`55 (33)
`14 (8)
`46 (28)
`18(11)
`22 (13)
`10(6)
`
`_
`
`,
`
`-
`'
`
`51 (31)
`16(10)
`
`102 (61)
`64 (39)
`
`147 (89)
`10 (6)
`9 (5)
`
`'
`
`55 (33)
`14(8)
`’47 (28)
`17(10)’
`23 (14)
`10(6)
`
`630.0 :1: 316.9
`9.90 i 0.74
`61.10i 14.88
`6.19 i 1.51
`
`'
`
`651.8 :1: 372.0
`’ 10.03 :1: 0.76
`61.01 :1: 15.40
`6.08 :t 1.54
`
`

`

`
`
`Baseline Phosphate Binder use
`150 (90)
`149 (90)
`Yes
`16 10
`16 10
`No
`
`
`
`
`Primary Efficacy Outcomes,
`
`_ iPTH Proportion of subjects with a mean iPTH value 5 250 pg/mL during the efficacy-
`assessment phase: The mean (SD) baseline iPTH concentration was 652 (372) pg/mL in the
`cinacalcet group and 630 (317) pg/mL in the placebo group. Significantly more subjects in the
`cinacalcet group (46%) compared with the placebo group (7%) achieved a mean iPTH
`concentration _<_ 250 pg/mL during the efficacy-assessment phase (p < 0.001). More cinacalcet-
`treated subjects in the lowest baseline iPTH strata achieved an iPTH concentration 5 250 pg/mL
`than subjects in the higher baseline iPTH strata: 65% in the 2 300 and S 500-pg/mL stratum,
`44% in the > 500 and '5 800 pg/mL stratum, and 9% in the > 800 pg/mL stratum (see table
`below). In the baseline Ca x P S 70 [mg/dL]2 strata, 49% of cinacalcet-treated subjects achieved
`an iPTH _<_ 250 pg/mL, compared with 37% in the > 70[mg/dL]2 strata. In the placebo group, the
`proportions of subjects within each baseline iPTH and Ca x P stratum who achieved the target
`iPTH concentration ranged fi'om 0% to 18% The primary endpoint was also analyzed separately
`by age (< 65, _>_ 65 years), sex, and race (black, white, other). Results were similar for all
`subgroups and were comparable to the primary analysis.
`
`
`
`
`______ 9113.191_____4-21.1163)
`10/69(1 4)
`,
`45/69 (65)
`1/46(2)
`1
`23/47 (49)
`
`1/64 2
`
`s70
`
`-
`
`0/10 0
`
`1
`
`A11
`
`A11
`_
`SQ
`1......
`All
`>70
`.
`.
`Overall
`‘
`est Statistics:
`2
`.
`.
`CMH StatISth (X )
`
`‘
`
`.
`
`71.62
`
`<0.001
`
`11.11
`
`11/12_3_g9_2_
`0/4g0)
`'11/165 7
`
`.
`
`15/41 (37
`76/166 46
`
`1
`
`i 39%
`
`Difference
`CinacaI-Plac
`95% CI
`31% 48%
`
`Odds Ratio
`Cinacal/Plac
`95% CI
`5.42 22.78
`
`Analysis by Dose Level: Cinacalcet treatment was titrated based on an individual subject’s
`iPTH response and tolerability. At the end of the study (Week 26), subjects were distributed
`across all dose levels of cinacalcet, with 36% of subjects receiving 180 mg (see table below). In
`the placebo group, 93% of subjects were at the ISO-mg placebo dose level.
`
`Page 99
`
`

`

`
`
`
`
`
`
`
`
`
`
`6 4
`
`1005)
`
`
`1
`1
`
`...6__(fl)e_,..1'~ V
`
`
`
`Secondary Efficacy Outcomes
`
`Proportion of subjects with a reduction from baseline in mean iPTH of Z 30%: A
`significantly greater proportion of subjects in the cinacalcet group (68%) compared with the
`placebo group (12%) had a 30% decrease from baseline in mean iPTH concentration during the
`efficacy-assessment phase (p < 0.001). The proportion of subjects in the cinacalcet group who
`achieved a 2 30% reduction in iPTH concentration was similar for all baseline iPTH strata: 67%
`in the Z 300 and S 500 pg/mL stratum; 73% in the >500 and S 800 pg/mL Stratum, and 61% in
`the > 800 pg/mL stratum (see table below). The proportion of cinacalcet-treated subjects who
`reached this endpoint waS‘also similar for both baseline Ca x P S 70 [mg/dL]2 strata, 66% of
`cinacalcet-treated subjects achieved an iPTH 5 250 pg/mL, compared with 76% in the >
`70[mg/dL]2 strata. In the placebo group, the proportions of subjects within each baseline iPTH
`and Ca x P stratum who achieved the target iPTH concentration ranged from 0% to 16%.
`
`E
`
`-
`
`
`Placebo
`Cmacalcet
`=165
`= 165
`
`9/51 18
`
`36/45 80
`
`_
`
`'
`
`
`
`>500 ands-800 ‘ S70
`
`-
`
`5
`
`1/12 8
`10/63 16
`6/45 13
`
`10/11 91)
`46/56 82
`33/37 89
`
`’
`S
`14/16 88
`1/16 6
`
`7/61 (11)
`47/53 (82)..
`M2/1gj(_13)_____._
`13/20£§§2.......
`7/10__(79),111111111111
`
`Page 100
`
`
`
`
`
`
`
`Dail dose m_ after titrationgweek 14) - n/Nl (%)_
`_
`30
`20/135
`15
`1/150 1
`
`-l-II
`_—II-Il
`21/150 14
`28/135 21
`118/150 79 =39/.135 29
`
`6_
`
`_
`
`
`

`

`
`Clinical Review Section
`
`iPTH Stratum
`
`Ca x P Stratum
`
`Placoeb ‘
`
`’
`
`Cinac_alcet
`= 165
`
`
`
`. All
`All
`
`E <70
`§>70
`
`est Statistics:
`
`17/112 15
`2/38 5
`19/150 13
`
`Difference
`Cinacal-Plac
`
`15.24, 58.48
`
`60% 77%
`
`Percentage change from baseline in mean Ca x P: The mean (SE) Ca x P value at baseline
`was 61.2 (1.2) (mg/dL)2 for subjects in both treatment groups. The mean Ca x P value during
`the efficacy-assessment phase was 49.9 (1.3) (mg/dL)2 for the cinacalcet group and 59.4 (1.2)
`(mg/dL)2 'for the placebo group. The mean Ca x P value was reduced by 17% in the cinacalcet
`group, compared with a 1% reduction in the placebo group (p < 0.001). Within each treatment
`group, percentage changes in mean Ca x P were consistent across all baseline iPTH stratum, with
`reductions ranging from 13% to 20% in the cinacalcet group and changes ranging from a
`decrease of 2% to an increase of 1% in the placebo group. In contrast, differences were observed
`across the baseline Ca x P strata. In the S 70 (mg/dL)2 strata, the mean Ca x P value decreased
`from baseline by 13% for subjects in the cinacalcet group, compared with an increase of 3% for
`subjects in the placebo group In the > 70 (mg/dL)2 strata, the Ca x P value decreased by 27%
`for subjectsm the cinacalcetgroup, compared with 10% for subjectsm the placebo group.
`
`a
`'1
`.
`. M”, -
`.
`.
`.
`_
`1.,
`,
`f3
`,l .
`.
`H ,6",
`3
`.A ”if;
`
`
`J
`Cinacalcet
`Placebo
`
`
`.
`m— = 165
`= 16
`
`Inn—mum's?“
`
`
`
`‘___-I--I
`__-1265 497
`14
`43-71354
`
`
`>500and<800 <70
`45
`1.46(2.53)
`
`
`
`
`17
`-3093 375
`
`——-7-I—M
`
`
`
`
`
`
`
`
`
`>70
`
`-9.65 399
`
`.
`
`__--'l-—-I
`_mm
`_—
` All
`Overall
`est Statistics:
`
`
`
`III-10.34 274 m -27.00 2.43
`-l6.69 2.09
`-0.68 1.86 ' 163 i
`
`
`
`
`
`
`
`Value
`P-value
`
`
`33.72
`< 0.001
`CMH Statistic ‘
`
`Change from baseline in self-reported cognitive functioning scale score: Changes in Self—
`reported Cognitive Functioning Scale Score From Baseline to the End of the Efficacy-assessment
`phase was conditional on achieving statistical significance for the key secondary endpoint.
`Statistical significance was achieved for the key secondary endpoint (p < 0.001), therefore this
`
`Page 101
`
`

`

`f C‘flffiNICAL REVIEW_
`
`. Clinical Review Section
`
`endpoint was tested. The mean (SD) baseline KDQOL Cognitive Functioning scale score for
`subjects in this study was 77.7 (19.3), which is similar to the baseline score of 82.4 for the
`Medical Outcomes Study population (n = 3,053) in which the scale was developed. During the
`efficacy-assessment phase, the mean (SE) change from baseline in the KDQOL Cognitive
`Functioning scale score was 0.6 (1.32) for the cinacalcet group and -1.6 (1.16) for the placebo
`group (p = 0.317).
`
`Tertiary Efficacy Outcomes
`Percentage changes from baseline in mean iPTH, serum calcium, and serum phosphorus
`
`@111: Mean (SE) baseline iPTH concentrations were similar between treatment groups: 653
`(29) and 630 (25) pg/mL for subjects who received cinacalcet and placebo,
`respectively. The mean iPTH concentration during the efficacy-assessment phase was 361 (29)
`pg/mL for the cinacalcet groupand 687 (32) pg/mL for the placebo group. The mean plasma
`iPTH concentration was reduced by 48% in the cinacalcet group, compared with an increase of
`9% in the placebo group (p < 0.001) (see table below). For the cinacalcet group, the mean
`percentage reduction in iPTH concentration in all baseline iPTH strata was 46% in the Z 300
`and S 500 pg/mL stratum; 55% in the 500 and S 800 pg/mL stratum; and 36% in the > 800
`' pg/mL stratum (see table below). The percentage reduction in iPTH concentration was similar
`across the baseline Ca x P strata (47% and 50% in the 5 70 [mg/dL]2 and > 70 [mg/dL]2 strata,
`respectively). For the placebo group, increases in iPTH concentrations within each baseline
`iPTH and Ca x P stratum ranged from 1% to 25%.
`
`
`
`
`
`
`>300and <500
`55 744456 5.60
`
`14
`-5400 811
`
`
`69
`-46.47 4.76
`
`
`
`3 5,00 and g 890
`
`
`
`
`
`
`
`
`
`_IIIIII
`----I--l
`
`
`
`
`
`.
`
`.
`14.99 4.85
`41
`>70
`- All
`—--l--I— .
`est Statistics:
`
`
`
`Value
`
`
`
`CMH Statistic .
`
`
`
`
`Calcium: Mean (SE) baseline serum calcium concentrations were similar between treatment
`groups: 10.0 (0.1) and 9.9 (0.1) mg/dL for subjects who received cinacalcet and placebo,
`respectively. The mean serum calcium concentration during the efficacy-assessment phase was
`9.2 (0.1) mg/dL for the cinacalcet group and 9.9 (0.1) mg/dL for the placebo group. The mean
`serum calcium concentration was reduced by 8% in the cinacalcet group, compared with a < 1%
`
`Page 102
`
`

`

`
`
`Clinical Review Section
`
`increase in the placebo group (p < 0.001) (see table below). For each treatment group, changes in
`. serum calcium were similar across all strata.
`
`ma
`
`am...
`
`.
`
`-
`
`.,
`
`,- ,
`
`..
`
`A
`
`>__3_OOand<500
`
`Cinacalcet
`_—-m--m-
`MISSIW
`
`”-552 102
`55 . 034 0.64
`14 ‘ ~8.51 1.39
`-0.40 1.19
`>70
`019 056 m -6-13 0.87
`—— 69
`>500and< 800
`570
`-011 0.65mm -7.61 1.32
`>70
`17
`-7.05 1.99
`
`est Statistics:
`
`-746110
`61
`009 056
`00-_ 62
`mm
`
`All
`Overall
`
`Phosphorus: Mean (SE) serum phosphorus Concentrations at baseline were similar between
`treatment groups: 6.1 (0.1) and 6.2 (0.1) mg/dL for subjects who received cinacalcet and
`placebo, respectively. The mean serum phosphorus concentration during the efficacy-assessment *
`phase was 5.4 (0.1) mg/dL for the cinacalcet group and 6.0 (0.1) mg/dL for the placebo group.
`The mean serum phosphorus concentration was reduced by 10% in the cinacalcet group,
`compared with a 1% reduction in the placebo group (p < 0.001). Within each treatment group,
`,
`percent changes from baseline in phosphorus were generally similar between baseline iPTH
`strata, with reductions ranging from 7% to 13% in the cinacalcet group and from 1% to 0% in the
`placebo group(see table below). In contrast, differences were observed between the baseline Ca
`x P strata. In the < 70 (mg/dL)2 strata, the mean phosphorus concentration decreased by 6% for
`subjects;1n the cinacalcet group, compared with a 2%increase in the placebo group. In the > 70
`(mg/dL)2 strata, the mean phosphorus concentration decreased by 20% and l 1% for subjectsin
`the cinacalcet and placebo groups, respectively.
`
`—_-m--m-
`Mum
`>300and<500
`203 4.08
`-4.81421
`
`
`14 -1235 4.80— >70 -16.66 3.56
` ._ -- . ..
`
`__ -... .-_..
`
`
`..
`69
`12.2.1347)
`>500 and: 800
`‘
`.
`.
`44
`-8.27 3.68
`17 1.25.52 3.87
`
`f
`
`.
`
`.
`
`
`
`
`
`Page 103
`
`

`

`
`
`
`
`
`'CaxPStratum
`=16
`..
`
`
`
`>70
`
`122 g 2.45 (2.23)
`41
`-10.88 2.67
`
`122 E
`41
`
`-6.43 (2.48)
`-20.08 2.47
`
`iPTH Stratum
`
`All
`All
`
`.
`
`
`
`'——--l 163
`‘ est Statistics:
`‘
`
`
`
`-9.86 2.01
`
`P-value
`0.001
`
`
`
`
`
`
` '
`
`Value '
`10.59
`
`1
`E.
`
`'
`
`
`
`Proportion of subjects with both a mean iPTH S 250 pg/mL and a reduction from baseline
`in mean Ca x P: Forty-two percent of subjects in the cinacalcet group compared with 5% in the
`placebo group had both a mean iPTH 5 250 pg/mL and a reduction from baseline in mean Ca x
`P during the efficacy-assessment phase, (p < 0.001). Since 46% percent of subjects had a mean
`iPTH S 250 pg/mL, approximately 91% of subjects who achieved an iPTH S 250 pg/mL also
`had reductions in Ca x P.
`'
`
`Efficacy Conclusions: The proportion of subjects who achieved a target iPTH
`concentration < 250 pg/mL (primary endpoint) was significantly greater in the cinacalcet
`group than in the placebo group (46% versus.7%; p < 0.001). A significantly greater
`proportion of subjects in the cinacalcet group (68%) compared with the placebo group
`(12%) had a 30% reduction in iPTH concentration (nominal p < 0.001). The mean iPTH
`concentration was reduced by 48% in the cinacalcet group, compared with a 9% increase
`in the placebo group (nominal p.< 0.001). Consistent reductions in iPTH concentrations
`occurred inall strata of baseline iPTH and Ca x P levels. The effects of cinacalcet on iPTH
`were independent of vitamin D sterol use or dose changes.
`
`V
`
`‘
`
`In the cinacalcet group, reductions in iPTH concentrations were accompanied by
`significant reductions in Ca x P levels. The mean Ca 11 P value in the cinacalcet group was
`reduced by 17% during the efficacy-assessment phase, compared with a 1% reduction in
`the placebo group (nominal p < 0.001). Reductions in Ca x P in the cinacalcet group
`resulted from reductions in both serum calcium (-8%) and phosphorus (-10%)
`concentrations (nominal p < 0.001, compared with placebo). In the placebo group,»mean
`serum calcium, phosphorus, and Ca x P remained at baseline levels throughout the study.
`
`No difference between treatment groups was observed for the change from baseline to the
`efficacy-assessment phase in the KDQOLTM Cognitive Functioning scale.
`,
`
`Safety
`
`Disposition: As shown in the table below, 93% of placebo-treated subjects and 93% of
`cinacalcet-treated subjects experienced adverse events during the study. Serious adverse events
`were equally distributed between the two groups. Adverse events leading to withdrawal from the
`study were higher in the cinacalcet-treated group (22%) compared with the placebo-treated group
`(5%).
`
`Page 104
`
`

`

` ‘
`
`Placebo
`
`Cmacalcet
`
`
`
`Sub'Ects evaluablefgr safety
`Deaths on stud ‘
`
`__
`
`_
`
`Serious adverse events
`
`
`
`.
`
`
`
`' includes one subject who died on Day 24 of the extension study, 20010240
`
`Exposure: A total of 330 (165 cinacalcet, 165 placebo) subjects received study medication (see
`table below). The mean (range) number of days of exposure to study drug was 148 (l to 199)
`days for the cinacalcet group and 163 (l, 203) days for the placebo" group. The mean (range)
`
`cumulative dose of cinacalcet was 11, 706 (
`” mg.
`
`. - w.
`J!»
`.
`.
`4:26» «.51
`x
`”WEEK
`as
`
`
`
`A».
`
`cinacalcet
`=165
`
`'
`
`Number of days of exposure
`
`
`
`
`
`
`
`
`Dosing Compliance (%) = 100 x (number of days dose taken / number of days prescribed).
`
`
`
`‘ Deaths: A total of 13 (7 in the placebo group and 6 in the cinacalcet group) deaths occurred
`during the study. Of the deaths occurring during the study, 6 (1 event in the placebo group and 5
`events in the cinacalcet group) were due to cardiac arrest. Other events occurring in the
`cinacalcet treated group include one event of cardiac failure. Events occurring in the placebo
`treated group included one each due to access hemorrhage, pulmonary edema, cerebral
`hemorrhage, myocardial infarction and renal failure. One death (in the placebo group) was due to
`unknown causes. Causes of death were consistent with this population’s baseline comorbid
`’ conditions and similar to causes of death in the general population of patients with ESRD.
`
`Serious Adverse Events: Serious adverse events‘were reported by 51 (31%) placebo-treated
`subjects and 47 (28%) cinacalcet-treated subjects (see table below). The most common serious
`adverse events were pneumonia (1 % of the placebo treated group and 5% of the cinacalcet
`treated group), non-cardiac chest pain (1 % of the placebo treated group and 3% of the cinacalcet
`treated group), sepsis (0 % of the placebo treated group and 3% of the cinacalcet treated group)
`and cardiac failure (1 % of the placebo treated group and 3% of the cinacalcet treated group).
`
`Page 105
`
`

`

`
`
`Subjects Receiving Dose
`Subjects Reporting SAEs
`Events:
`
`165
`51 (31)
`
`.
`
`.
`
`. Gastrointestinal
`Liver/ Biliary
`Nervous
`Cardiovascular
`Heart Rate / Rhythm
`Myo/Endo/Pericardial
`Respiratory
`Body as a whole
`Endocrine/Metabolic
`Musculoskeletal
`Infectious
`Blood and Lymphatic
`' Skin and Appendages
`Urinary Disorders
`Vascular Disorders
`Vision Disorders
`Ps chiatric
`
`-
`
`‘
`
`'
`
`'
`
`’
`
`165
`47 (28)
`
`11 (7)
`1 (I)
`8(5)
`5(3)
`8 (5)
`4 (2)
`6
`9 (5)
`1 (1)
`4 (2)
`3 (2)
`
`2 (1)
`0 (0)
`8 (5)
`
`9(5)
`0(0)
`5 (3)
`3 (2),
`3 (2)
`5 (3)
`8 (5)
`12 (7)
`2(1)
`8 (5)
`9 (5)
`_
`0 (O)
`1 (l)
`8 (5)
`
`'
`
`.
`
`'
`
`Adverse Events Leading to Withdrawal: A total of 46 subjects had adverse events leading to
`‘ withdrawal from the study [37 (22%) from the cinacalcet group and 9 (5%) from the placebo
`group]. The most common adverse events leading to withdrawal were: vomiting (7%,0%),
`nausea (6% ,,0%) diarrhea (2%,1%), dyspepsia (2%,0%), fatigue (2%,0%) and abdominal pain
`(2%,0%). One subject from the cinacalcet group withdrew from the study because of
`hypocalcemia.
`
`Adverse Events Leading to Dos'e Alteration: A total of 74 subjects had adverse events leading
`to dose alteration [54 (33%) from the cinacalcet group and 20 (12%) from the placebo group].
`The most common adverse events were gastrointestinal [40 (24%) from the cinacalcet group and
`9 (5%) from the placebo group], predominantly nausea and vomiting. One subject in the
`cinacalcet group and no subjects in the placebo group required dose alteration because of
`hypocalcemia.
`
`Adverse Events: A total of 93 % of subjects in the both groups reported at least 1 adverse event
`duringthe study (see table below). The most common adverse events were VOmiting (39%
`'
`cinacalcet, 13% placebo), nausea (31% cinacalcet, 19% placebo), diarrhea (16% cinacalcet, 18%
`placebo), myalgia (16% cinacalcet, 16% placebo), and headache (15% cinacalcet, 22% placebo).
`Adverse events with a > 5% difference between treatment groups included vomiting (39%
`cinacalcet, 13% placebo), nausea (31% cinacalcet,19% placebo), headache (15% cinacalcet,
`22% placebo), hypotension (8% cinacalcet,13% placebo), and upper respiratory infection (3%
`cinacalcet, 11% placebo).
`
`Page 106
`
`

`

` Subjects Receiving Dose
`
`Subjects Reporting AEs
`Events:
`
`153 (93)
`
`165
`153 (93)
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`62 (38)
`117 (71)
`'3 (2) '
`58 (35)
`27 (16)
`23 (14)
`8 (5)
`42 (25)
`8 (5)
`56 (34)
`14(8)
`8 (5)
`28 (17)
`9 (5)
`3 (2)
`l3 (8)
`
`'
`
`.
`
`'
`
`,
`
`.
`
`,
`
`'
`
`,
`
`’
`
`’
`
`68 (41)
`Body as a whole
`87 (53)
`Gastrointestinal
`0(0)
`Liver/ Biliary
`62 (38)
`Nervous
`.
`28 (17)
`Cardiovascular
`16 (10)
`Heart Rate / Rhythm
`12 (7)
`Myo/Endo/Pericardial
`50 (30)
`Respiratory
`5 (3)
`‘ Endocrine/Metabolic
`63 (38)
`Musculoskeletal
`15 (9)
`Infectious
`7 (4)
`Blood and Lymphatic
`_ 34 (21)
`'Skin and Appendages
`6 (4)
`Urinary Disorders
`5 (3)
`Reproductive
`17 (10)
`Vascular Disorders
`12 (7)
`.
`.
`Vision Disorders 7
`
`Hearing / Vestibular
`Ps chiatric
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Adverse Events of Special Interest:
`
`Convulsionsz-Three serious adverse events of convulSions and l serious adverse event of status -
`
`epilepticus were reported in the cinacalcet group. No reports of seizure activity occurred in the
`placebo group.
`
`'
`
`GI Adverse Events: Gastrointestinal adverse ’events are common with cinacalcet treatment.
`
`Serious adverse events related to the gastrointestinal system were reportedfor 7% of subjects in
`. the cinacalCet group and 5% of subjects in the placebo group. Nausea was reported in 31% of
`cinacalcet-treated patients and 19% of placebo treated patients. Vomiting was reported in 39% of
`cinacalcet-treated patients and 13% ofplacebo-Heated patients. Diarrhea was reported in 16% of ‘
`cinacalcet-treated patients and 18% of placebo treated patients. Nausea was considered severe in
`4% of subjects in the cinacalcet group and 0% of subjects in the placebo group. Vomiting was
`considered severe in 1% of subjects in the cinacalcet group and 0% of Subjects in the placebo
`group. GI hemorrhage was reported in l (1%) cinacalcet-treated patient and 8 (5%) placebo-
`treated patients. Dyspepsia was reported in 12 (7%) of cinacalcet-treated subjects and 6 (5%) of
`placebo-treated subjects. Gastric ulcer was reported in 2 (1%) cinacalcet-treated subjects and 1
`(1%) placebo-treated subject. There were 3 (2) reports of gastritis in the cinacalcet group and l
`( 1%) report in the placebo group. Esophagitis was reported in one subject in the cinacalcet-
`treated group.
`'
`‘
`
`Cataracts: One subject in the placebo group developed cataracts during the study.
`
`'
`
`Laboratory: Safety laboratory assessments were performed at screening and follow-up.
`
`Page 107
`
`

`

`
`. Clinical Review Section
`
`Hypocalcemia was reported as an adverse event in 3% of subjects in each treatment group. A
`confirmed serum calcium < 7.5 mg/dL (2 consecutive measurements) during the study occurred
`in 5% and 2% of subjects in the cinacalcet and placebo groups, respectively. No other trends
`indicative of other treatment-related effects in
`
`clinical chemistry, hematology, 1,25(OH)2D3, or Hb Alc were noted. Shifi tables also
`demonstrated no evidence of a treatment effect;
`'
`
`Other Safety Tests:
`Vital Signs: Mean blood pressure measurements were stable throughout the study and did not
`differ between treatment groups.
`
`-
`
`ECGs: ECGs were collected predialysis, at approximately nadir drug concentrations.
`Investigator interpretation of ECGs was categorized on the case report form as normal;
`abnormal, but not clinically significant; or abnormal, clinically significant. Approximately one-
`half of the subjects (58% cinacalcet, 53% placebo) had an abnormal ECG at baseline. Of those
`subjects without clinically significant ECG abnormalities at baseline, 2 subjects (1%) in the
`cinacalcet group and 8 subjects (5%) in the placebo group had findings that were considered
`clinically significant at the end of the study. One of the subjects who received cinacalcet had
`first-degree atrioventricular block, and the other had a partial right bundle branch block and a
`prominent T wave. Of the 8 subjects in the placebo group, 3 subjects had no discemable changes
`from the baseline ECG report, and 1 subject each had atrial fibrillation, a prolonged QT interval,
`lefi ventricular hypertrophy, tachycardia, or peaked T waves).
`’
`
`QT intervals corrected for heart rate using Bazett’s (QTcB) and Fridericia’s (QTcF) correction
`formulae were measured at baseline and Weeks 14 and 26. At Weeks 14 and 26, the cinacalcet
`group had a mean change in QTcB that was 6.4 and 1.8 msec greater than the placebo group,
`respectively. When the QT interval was corrected using the Fridericia’s formula, similar
`differences in mean change were observed. When subjects were categorized with regard to -
`change in QTc from baseline (<30, 30 to 60, > 60 msec), similar proportions of subjects had an
`increase of > 60 msec at all time points, regardless of the correction formula used. Increases in
`QTc of 30 to 60 msec were observed at Week 14 in 16% and 6% of subjects in the cinacalcet and
`placebo group, respectively. At Week 26, increases in QTcB of 30 to 60 msec were observed in
`, 14% and 21% of the cinacalcet and placebo group, respectively. No notable differences between,
`treatment groups were observed in the occurrence of an absolute QTc > 500 msec at any time
`'point during the study.
`'
`'
`
`a2:
`—-_
`
`163
`163
`
`421.1
`415.2
`Mean
`SE
`2.6
`2.2
`
`413.0
`
`'w 422.0
`
`Page 108
`
`

`

`
`
`Clinical Review Section
`
`$4143}.
`
`Week14
`
`'
`
`
`
`415.0
`Median
`127
`Week 26
`
` Mean 421.4
`SE
`3.1
`3.4
`416.0
`156
`End of Stud
`
`Mean
`422.9
`417.0
`
`SE ~
`Median
`
`4
`
`2.7
`417.5
`
`2.8 -
`416.0
`
`The proportion of subjects with at least 1 absolute increase in QTcB beyond the upper limit of
`normal (450 msec [men] and 470 msec [women]) was slightly higher in the cinacalcet group
`compared with the placebo group at Week 14 (12% versus 8%, respectively), but was higher in
`the placebo group compared with the cinacalcet group at Week 26 and end of study (13% versus
`7% and 14% versus 8%, respectively). For the subjects with an increase beyond the upper limit
`of normal, the mean increase in QTcB was 43 msec for the cinacalcet group and 33 msec for the
`placebo group at Week 14, and 45 msec for both groups at Week 26.
`1
`ea
`_
`.
`r75
`(xvz'
`r 6:3
`9;»:-
`6"
`
`,
`
`’1
`
`..
`
`3?
`
`1,,
`
`t
`
`.
`
`
`lacebo
`‘
`’
`Cinacalcet
`
`(135101)
`n/Nl %
`
`(3:291)
`n/NI %
`
`.
`
`69/141 49
`
`53/129 41
`
`Week 14
`Decrease
`
`~
`
`.,_.!“_°T_e§5£<_3m¢£__-.
`
`Increase 30-60 msec
`Increase > 60 msec
`Week 26
`
`
`
`Decrease
`Increase<30msec
`
`58/125 46
`38/125 30
`
`44/102 43
`, 41/102 40
`
`Increase 30-60 msec
`
`26/125 21
`
`.
`
`14
`14/102
`1/102 1
`
`End of Study
`Decrease
`Increase < 30 msec
`
`, P
`
`70/154 45
`50/154 32
`30/154 19
`
`‘
`
`66/149 44
`60/149 40
`18/149
`12
`
`.— 3/154 2
`Maximum Durin_ Stud
`
`
`Increase < 30 msec
`
`_....
`Increase 30—60 msec
`!
`Increase > 60 msec
`i
`
`3/149 2
`
`31/149 ( 21
`
`’
`
`.
`
`Page 109
`
`

`

`
`
`Clinical Revi