`
`
`
`. Clinical Review Section
`
`
`
`Stu 20000188: Summa
`
`of Exosure to Stud Dru
`
`__ cinacalcet
`— =29]
`
`
`
`,
`
`Dosing Compliance (%) = 100 x (number of days dose taken / number of days prescribed).
`
`Deaths: Among the 5 deaths that occurred in the study population, four occurred during the
`study and one was reported afier the database lock. 0f the deaths occurring during the study, 2
`were due to cardiac arrest (1 event each in the cinacalcet and placebo groups), 1 was due to
`cerebrovascular disorder (in the cinacalcet group), and l was due to unknown causes (in the
`placebo group). One death, due to hemorrhagic bowel ischemia and secondary lactic acidosis (in
`the placebo group) was reported afier database lock. 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 26 (26%) placebo-treated
`subjects and 80 (27%) cinacalcet—treatedsubjects (see table belOw). The most common serious
`adverse events were dyspnea (0 % of the placebo treated group and 2% of the cinacalcet treated
`group), GI hemorrhage (0 % of the placebo treated group and 2% of the cinacalcet treated
`group), peripheral gangrene (0 % of the placebo treated group and 2% of the cinacalcet treated
`group), pulmonary edema (2 % of the placebo treated group and 1% of the cinacalcet treated
`
`
`
`Subjects Receiving Dose
`Subjects Reporting SAEs
`Events:
`‘
`Gastrointestinal
`Liver/ Biliary
`, Nervous
`Cardiovascular
`Heart Rate / Rhythm
`Myo/Endo/Pen'cardial
`Respiratory
`Body as a whole
`Endocrine/Metabolic
`Musculoskeletal
`'
`Infectious
`Blood and Lymphatic
`Skin and Appendages
`Urinary Disorders
`Vascular Disorders
`Vision Disorders
`Ps chiatric
`
`‘
`
`_
`
`.
`
`‘
`
`'
`
`'
`
`-
`
`3 (3)
`0 (0)
`3 (3) '
`l (1)
`6 (6)
`7 (7)
`5 (5)
`7 (7)
`3 (3)
`3 (3)
`1 (1)
`l (l)
`l (l)
`0 (0)
`0 (0)
`
`_
`
`-
`
`.
`
`26 (26)
`
`i
`
`80 (27)
`
`,
`
`23 (8)
`2 (1)
`9(3)
`9(3)
`4 (l)
`8 (3) ,
`l9 (7)
`18 (6)
`4 (l)
`6 (2)
`12 (4)
`.4 (l)
`4 (1)
`3 (1)
`9 (3)
`
`,
`
`'
`
`,
`
`‘
`
`Adverse Events Leading to Withdrawal: A total of 47 subjects withdrew from the study due to
`adverse events [39 (13%) from the cinacalcet group and 8 (8%) from the placebo group]. The
`
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`
`Clinical Review Section
`
`most common adverse events were (cinacalcet, placebo) nausea (30%, 22%), diarrhea (24%,
`19%), vomiting (23%, 12%), upper respiratory infection (18%, 13%), headache (17%, 12%), and
`myalgia (15%, 14%).The rate of withdrawal due to adverse events was similar between patients
`receiving hemodialysis and peritoneal dialysis. Adverse events that most commonly resulted in
`withdrawal involved the GI body system, predominantly nausea (7% cinacalcet, 3% placebo),
`vomiting (3% cinacalcet, 1% placebo), and diarrhea (2% cinacalcet, 0% placebo).
`Adverse Events: Ninety-one percent of subjects in the cinacalcet group and 93% of subjects in
`the placebo group reported at least 1 adverse event during the study (see table below). The most
`common adverse events (2 15% in either treatment group) were (cinacalcet, placebo) nausea
`(30%, 22%),diarrhea (24%, 19%), vomiting (23%, 12%), upper respiratory infection (18%,
`13%), headache (17%, 12%), myalgia (15%, 14%), and abdominal pain (12%, 18%). In addition,
`adverse events that occurred with a 2 5% difference between treatment groups included
`(cinacalcet, placebo) abdominal pain (12%, 18%), asthenia (8%, 2%), hypotension (7%, 12%),
`and wound (5%, 0%).
`‘
`
`,
`
`
`
`,
`
`,
`
`94 (93)
`
`47 (47)
`53 (52)
`0(0)
`28 (28)
`18 (l 8)
`17 (17)
`11 (1 l)
`43 (43)
`8 (8)
`39 (39)
`7 (7)
`10 (10)
`20 (20)
`8 (8)
`4 (4) '
`7 (7)
`6(6)
`
`266 (91)
`'
`
`154 (53)
`187 (64)
`3 (l)
`114 (39)
`46 (16)
`22 (8)
`17 (6)
`124 (43)
`22 (7)
`100 (34)
`26 (9)
`' 29 (10)
`64 (22)
`24 (8)
`8 (3)
`25 (9)
`17 (6)
`
`.
`
`"
`
`Subjects Receiving Dose
`Subjects Reporting AEs
`Events:
`
`Body as a whole
`Gastrointestinal
`Liver/ Biliary
`Nervous
`Cardiovascular
`Heart Rate 7 Rhythm
`Myo/Endo/Pericardial
`Respiratory
`Endocrine/Metabolic
`Musculoskeletal
`Infectious
`Blood and Lymphatic '
`Skin and Appendages
`Urinary Disorders
`Reproductive’
`Vascular Disorders
`Vision Disorders
`Hearing /’Vestibular
`Ps chiatric
`
`‘
`
`*
`
`’
`
`.
`
`‘
`
`.
`
`_
`
`Adverse Events of Special Interest:
`
`Convulsions: Three (1%) subjects in the cinacalcet group and no subjects in the placebo group
`discontinued the study because of convulsions. A 32-year-old female receiving peritoneal
`dialysis with past medical history significant only for hypertension suffered convulsions at Week
`8 (60-mg cinacalcet dose level; serum calcium of 8.5 mg/dL) and Week 10 (90-mg cinacalcet
`dose level; serum calcium of 9.6 mg/dL). Baseline serum calcium was 10.0 mg/dL and baseline -
`iPTH was 621 pg/mL. No on-study serum calcium values were below the normal range. A 62—
`year-old male receiving hemodialysis with past medical history significant for convulsions (not
`receiving anti-convulsant medication at baseline), hypertension, cerebrovascular accident, and
`
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`

`

`
`
`CliniCal Review Section
`
`left ventricular hypertrophy experienced convulsions during week 16 (90-mg dose level; serum
`calcium of 9.3 mg/dL). Baseline serum calcium was 9.3 mg/dL and baseline iPTH was 455
`p.g/dL A local laboratOry reported an uncorrected serum calcium level of 7.4 mg/dL 1 dayafier
`the event. Corrected serum calcium ranged from 7.7 mg/dL to 9.3 mg/dL during the study. A
`28-year-old female receiving hemodialysis with past medical history significant for intermittent
`convulsions (recently treated with Dilantin), hypertension, and asthma experienced convulsions
`during Week 5 (60-mg cinacalcet dose level; serum calcium 7.4 mg/dL) and Week 7 (60-mg
`cinacalcet dose level; serum calcium 8.8 mg/dL). Baseline serum calcium was 9.6 mg/dL and
`baseline iPTH was 1788 pg/dL. At the time of the first episode of convulsions, the Dilantin
`level was below normal (8 umol/L; target therapeutic range = 40 to 80 umol/L). At the time of
`the second episode of convulsions, study drug had been withheld for 19 days. Records indicate
`that Dilantin dosing was being adjusted and the investigator attributed the convulsions to
`noncompliance with Dilantin or a drug interaction between Dilantin and Coumadin .
`
`GI Adverse Events: Gastrointestinal adverse eventsare common with cinacalcet treatment.
`Nausea was reported in 30% of cinacalcet-treated patients and 22% of placebo treated patients.
`Vomiting was reported in 23% of cinacalcet—treated patients and 12% of placebo treated patients.
`Diarrhea was reported in 24% of cinacalcet-treated patients andl9% ofplacebo treated patients.
`GI hemorrhage was reported in 4% of cinacalcet-treated patients and 0% of placebo treated
`patients. Dyspepsia was reported in 9% of cinacalcet—treated patients and 11% of placebo treated
`patients. There was one report each. of esophagitis and gastritis in the cinacalcet group and no
`reports in the placebo group.
`
`Cataracts: Cataract formation associated with cinacalcet use was reported in animal studies.
`There were no reports of cataracts in this trial.
`
`‘ Laboratory: Safety laboratory assessments were performed at screening and follow-up.
`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 trends indicative
`of treatment-related effects in clinical chemistry and hematology were noted across other
`laboratory parameters. Shifi tables also demonstratedno evidence of a treatment effect.
`
`Laboratories of Special Interest: In response to the l-year monkey toxicology findings, an
`evaluation of thyroid and gonadal function was includedin this study. The primary objective of
`this analysis was to determine whether subjects receiving cinacalcet were at increased risk for
`developing thyroid or gonadal dysfunction. The following hormones were measured at study
`entry (baseline), week 16, and week 26 in subjects-receiving cinacalcet or placebo: TSH, free T4, '
`tOtal and free testosterone, LH and FSH. TSH and free T4 hormone levels were assessed for all
`subjects. Total and fi'ee testosterone, LH, and FSH levels were assessed for men only.
`'
`
`The criteria used to define hyperthyroidism, hypothyroidism, and hypogonadism are provided in
`the table below. The definitions of hyperthyroidism and hypothyroidism were consistent with
`standard medical practice. Due to the lack of uniform clinical criteria, Amgen defmed
`hypogonadismas a total testosterone < 200 mg/dL and a 25% reduction from baseline.
`
`4 Page 127
`
`

`

`
`
`Clinical Review Section
`
` IIIIIIIIIIIIIIIIIIIII
`
`0.32 to 5 p IU/mL
`0.7 to l 9 ng/dL
`350 to. 1030 ng/dL
`52 to 280 pg/mL ‘
`2 to 12 mIU/rnL
`l to 15 mIU/mL
`
`TSH
`T4
`Total Testosterone
`Free Testosterone
`LH
`
`‘Norrnal ranges for total and free testosterone, LH, and FSH are for ‘
`males.
`.
`
`
`
`ELaborato Definrtron
`Condrtron
`IIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIII
`IIIEIIIiIIIIIIIIIIIIIIIIIIIIIIIIIiSHEIIIEIIIIIIIIIIIIIIIIIII
`, Hypogonadism
`i Total testosterone < 200 ng/mL and 25% reduction from
`baseline in total testosterone
`‘Diagnostic criteria had to be met at both weeks 16 and 26 (see Methods).
`
`Assessment of Thyroid Function
`T___SH: As shown1n the table below, baseline TSH levels were in thelow end of the normal range
`- in both treatment groups. TSH1n female subjects receiving cinacalcet at baseline and week 16
`was due to very high levels in 3 subjects. Two subjects completed the trial, one of whom was
`subsequently treated with thyroid hormone. The third subject was withdrawn because of an
`administrative decision.
`
`
`
`Females
`
`Placebo
`
`Cinacalceti. Placebo
`
`Cinacalcet
`
`
`
`
`hfimn
`180
`IIIIIIIIIIIIIIIIIIIIIIIIII
`IEJIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIII
`
`
`
`145
`
`'
`
`152
`
`The incidence of subjects with TSH levels outside the normal range at each time point is shown
`in the table below. In both treatment groups, 7 - 8% of subjects had TSH levels outside the
`normal range at baseline. The percentage of subjects with abnormal TSH levels remained stable
`throughout the study and was similar betWeen treatment groups. Only a few subjects in either
`treatment group had normal baseline TSH levels that subsequently became abnormal.
`
`Pagel28
`
`

`

`
`
`
`
`
`
`
`——
`_'—‘—'_-N__
`
`
`12 4
`
`___1_2 4 m..-
`NA
`“m.
`H—‘
`
`”N
`\‘NW—
`onO \O:7 2)
`_72 L92)_
`
`Aw
`out»
`N‘uw NA-b
`
`Within normal range
`Above normal ran 6
`
`.1-
`
`
`
`821.93)
`
`
`
`
`
`
`
`CLINTCAL REVIEW .
`
`Clinical Review Section
`
`
`
`
`
`Above normal ran-e
`Below normal range
`Normal at baseline / above normal mmc at week 16 or 26
`Normal at baseline / below normal ran-e at week 16 or 26
`
`Nomtal at baseline / below normal ran - e at week 16 or 26
`
`
`
`Free Thjgoxine.e' A summary of free T4 levels at baseline, week 16, and week 26 in cinacalcet
`and placebo treated subjects13 provided1n the table below. Free T4 levels were in the low
`normal range at baseline and throughout the study1n both treatment groups.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Eleven percent of subjects receiving cinacalcet and 15% of 'subjectsreceiving placebo had free
`T4 levels below the normal range at baseline (Table 6). The percentage of subjects with low free '
`T4 levels remained stable throughout the study and was similar between treatment groups. Four‘
`to 6% of subjects1n each treatment group had normal baseline levels that were subsequently
`below normal during the study.
`
`
`
` _ Baselme Week 16 Week 26
`
`
`9216
`Cinacalcet N %
`243
`
`
`Within normal range
`Below normal muse ..................................................................................................
`,_._;.919L(§L__
`
`
`
`
`
`
`Normal at baseline / below normal rangeeat week 16 or 26
`NA
`
`
`
`
`
`
`Page 129
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`

`

` ;
`
`Clinical Review Section
`
`—
`ngfik
`——_
`Placebo-N4 %
`-
`' “—-
`'
`'
`77 89
`
`-
`
`3 4
`
`67 86W__1_‘}_L1_§)
`
`NA
`
`5 6
`
`The proportion of subjects With both TSH and free T4 levels outside of the normal range at each
`time point is presented in Table 7. In'the Cinacalcet group, there were 4 (1%) subjects at baseline
`with elevated TSH and low free T4 levels; '2 of these subjects also had elevated TSH and low
`free T4 levels at week 16. No subject in either group met the definition of hyperthyroidism or
`hypothyroidism during the study (i.e., elevated TSH and low free T4 levels at both weeks 16 and
`26).
`
`
`
`Week 16 and—26
`
`
`
`
`Week 16 and 26
`’
`_
`_
`0/ 77 (0). 0/21591
`
`TSH < 0.32 E lU/mL and free T4 > 1.9 ngZdL . N §n%)
`N (n%)
`Baseline
`0/9610)
`0/284 0
`
`0/ 87 (0)
`‘* 0/243(0 )_
`;
`
`COMMENT: The majority of subjects in both treatment groups exhibited low to low-
`'normal free T4 levels with normal TSH levels, which is consistent with the sick euthyroid
`profile characteristic of patients with ESRD. No subject.11 either group met the definition
`of hyperthyroidism or hypothyroidism during the study.
`
`Assessment of Gonadal Function
`
`Total Testosterone: Total testosterone levels were below the normal range (< 350 ng/dL) at
`baselinein both treatment groups (298 ng/dLm the placebo-treated group and 327 ng/dL1n the
`cinacalcet-treated group). Total testosterone levels were significantly reduced in the Cinacalcet
`group when compared to placebo (see table b’elbw). At Week 16, the mean percent change from
`baseline in the Cinacalcet group was -37.80 compared to] 1.73 1 in the placebo group (p=0.003).
`At Week 26, the mean percent change from baseline in the Cinacalcet group was ~50.97
`compared to -l .58 in the placebo group (p=0.002).
`
`
`
`
`
`Page 130
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`

`
`Clinical Review Section
`
`4.
`_,
`.’:.
`..
`.ds;
`m. ééw
`.v-ng-
`— P130610
`I'ercent Chan e from Baseline
`Week 16
`
`n 51
`
`.
`
`Mean
`SD
`Median
`0 value
`Week 26
`Mean
`SD
`
`p
`
`l
`
`.
`
`i
`
`*
`
`11.73
`97.42
`23.00
`
`n 48
`-1.58
`119.28
`
`-
`
`.
`
`
`
`1 cinacalcet
`
`.
`
`n 141
`
`- 37.80
`122.56
`-33.00
`
`0.003
`
`n 125
`-50.97
`143.61
`
`{v
`
`The incidence of subjects with baseline normal total testosterone levels who developed levels
`below normal range at each time point is shown in the table below. A significant number of
`subjects who were normal at baseline developed sub—normal testosterone levels when treated
`with cinacalcet.
`
`
`
`
`Cinacalcet
`24/61 39
`g:
`26161443
`Placebo
`4/20 20
`i
`2/_29_L10
`'
`
`
`
`
`. value from Fisher’s Exact test
`0.175
`0.007
`3
`
`
`
`Free Testosterone: Free testosterone levels were below the normal range (< 52 pg/dL) at baseline _
`in both treatment groups (64 pg/dL in the placebo-treated group and 68 pg/dL in the cinacalcet-
`} treated group). Free testosterone levels were significantly reduced in the cinacalcet group when
`compared to placebo (see table below). At Week 16, the mean percent change from baseline in
`the cinacalcet gronp was -15.51 compared to -4.97 in the placebo group (p=0.005). At Week 26,
`the mean percent change from baseline in the cinacalcet group was -20.38 compared to -14.61 in
`the placebo group (p=0.06l).
`
`$.11“
`__— ‘
`otal Testosterone (11le _____
`i Q‘1=57)
`1
`(N=16§)
`Baseline
`
`_m—
`» SD
`1
`37.92
`
`62-50
`
`
`
`xi
`I' ercent Change from Baseline
`n 51
`Week 16
`
`
`
`
`
`n 140
`
`1
`
`Page 131
`
`

`

`
`;
`iii-C“ _'NICAL REVIEW A
`
`Clinical Review Section
`
`
`
`The incidence of subjects with baseline normal free testosterone levels who developed levels
`below normal range at each time point is shown in the table below. A significant number of
`subjects who were normal at baseline developed sub-normal free testosterone levels when treated
`with cinacalcet.
`
`
`
`
`
`— n/N %
`
`
`mm-
`
`
`
`Gonadotropin Levels: Baseline levels of LH were similar in the two groups: 11.5 mIU/ml in the
`placebo—treated group and 11.2 mIU/ml in the cinacalcet-treated group. The mean values at
`Week 26 were 12.3 mIU/ml and 9.9 mlU/ml in the placebo and cinacalcet groups, respectively.
`Of the cinacalcet-treated subjects with normal LH levels at baseline, 2% had elevated LH levels
`at Week 26. Among subjects receiving placebo with normal LH levels at baseline, 11% had
`elevated LH levels at Week 26. Baseline levels of FSH were similar in the two groups: 9.7
`mIU/ml in the placebo-treated group and 9.5 mIU/ml in the cinacalcet—treated group. There were
`very small, insignificant changes in the levels of FSH from baseline to Week 26 in both groups.
`Very few subjects (1 to 2) in either treatment group had normal baseline FSH levels that
`subsequently were above the normal range at Week 26.
`
`
`
`
`
`MIKE-ING-
`
`
`
`Normal baseline / above normal ran_e Week l6 or 26
`NA
`6 13
`
`
`
`
`0 (0)
`Normal baseline / below normal range Week 16 or 26
`NA
`i
`
`4
`
`i i“
`
`‘
`
`Luteinizin_ Hormone
`Cinacalcet - N %
`Within normal range ~
`Above normal rane
`__mo-M
`Normal baseline / above normal ran _e Week 16 or 26
`[
`NA ”6-..-
`
`1
`
`Week 16
`
`Week 26
`
`
`
`
`__-El_
`-124'71I-l14 '73I-106'76I
`
`
`
`n—m-nu
`
`
`
`
`
`
`
`Page 132
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`

`

`
`
`Clinical Review Section
`
`,
`
`Week 16
`
`~
`
`l"""""""NA
`
`175 —-]11-
`Cinacalcet- N %
`
`Within normal range
`149 ( 85
`135 86
`124 89
`Above normal ran-e
`26N15
`22
`14
`
`Normal baseline / above normal rane Week 16 or 26
`25(1) E
`Placebo- N %
`61
` 9
`Above normal range
`Normal baseline / above normal ran
`
`,__,_§i_02_4)____- “(.1218
`l 2
`
`(L5)
`
`The proportion of subjects in each treatment group who developed a total testosterone level of <
`p 200 mg/dl and had a > 25% reduction from baseline, 4% of placebo subjects and 18% of
`cinacalcet subjects met these criteria at Week 26. Notably, most of the cinacalcet subjects with
`total testosterone < 200 mg/dL and a > 25% reduction from baseline at either week 16 or week
`26 had low testosterone levels at baseline. The changes in FSH and LH for subjects meeting
`these criteria were also similar in both treatment groups. Cinacalcet treated subjects with a total
`testosterone < 200 mg/dL and a > 25% reduction from baseline had mean percent changes in LH
`of- 18% and -10% and FSH of —4% and -2% at week 16 and week 26, respectively Similarly,
`placebo treated subjects with a total testosterone < 200 mg/dL anda > 25% reduction from
`baseline had mean percent changes1n LH of— 13% and- 13% and FSH of -3% and -20% at week ~
`16 and week 26, respectively.
`.
`
`COMMENTS: Chronic renal failure is known to cause hypothalamic-pituitary dysfunction
`affecting the sex steroid axis. Gonadal dysfunction in uremia also occurs. As testosterone
`levels fall, gonadotropin levels generally increase. In addition to evidence of defects in »
`pituitary and gonadal function, there are indicators suggesting the importance of
`alterations in hypothalamic regulation of pituitary-gonadal function in the pathogenesis of
`uremic hypogonadism. Cinacalcet is a calcimimetic agent that acts as a modulator of the
`calcium-sensing receptor (CaR). The calcium-sensing receptor has been shown to exist on
`anterior pituitary cells9 as well as in the testes themselves1 .The etiology of the decrease1n
`serum testosterone levels with cinacalcet treatment’1s unclear. Long term sequelae of
`. hypogonadism include infertility, osteopenia and impaired physical function.
`
`Other Safety Tests:
`
`‘ Vital Signs: Mean blood pressure measurements were stable throughout the study and did not
`differ between treatment groups
`-
`
`ECGs: Of those subjects without clinically significant ECG abnormalities at baseline, 13 (5%)
`subjects in the cinacalcet group and no subjects in the placebo group had clinically significant
`
`9 Zivadinovic D, eta]. Cell-type specific messenger functions of extracellular calcium in the anterior pituitary.
`Endocrinology 2002. 143(2):445—455.
`'0 Adebanjo 0A, et.al.. The effect of extracellularly applied divalent cations on cytosolic Ca2+ in murine leydig-
`cells: evidence for a Ca2+-sensing receptor. 1998. J Physiol 513 (Pt2):399—410.
`
`Page 133
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`

`

`
`
`Clinical Review Section
`
`abnormal ECG findings at the end of study. One subject was noted to have a prolonged QT
`interval, with a 33 and 31 msec increase in QT interval, corrected for heart rate by Bazett’s
`formula (QTcB) at weeks 18 and 26, respectively. The subject completed the duration of the
`study and no adverse events potentially related to prolonged QT interval were reported.
`
`QT Interval: QT intervals corrected for heart rate using Bazett’s (QTcB) correction formula was
`measured at baseline and weeks 18, 26, and end of study. The mean QTcB interval was slightly ~
`higher in the cinacalcet group (426 msec) than the placebo group (423 msec) at baseline(see‘
`table below). The mean maximum increase during the study was 14.10 msec in the placebo-
`treated group compared to 20.05 msec in the cinacalcet-treated group. When the QT interval was
`corrected using Fn'dericia’s formula, the results were similar to those observed using Bazett’s
`correction formula.
`'
`
`
`
`
`
`
`422.87
`.
`42392
`
`347*
`1151
`,
`
`416.00__fl_
`424.00
`
`n(76)__ i
`n(229)
`425.39
`_§
`43§_.l6
`
`444
`2.29
`'
`4.1209
`434.00
`ngs)__
`n(213)
`421,67..."
`...€1_3_8;!_3.-.__
`
`_____ WM _ N4.48"
`2.31
`425.00”
`436.00
`M— n 88 .
`n 261
`- -_ 427.92
`435.22
`__
`3.85
`2.13
`425.00
`434.00
`
`E
`
`As outlined in the table below, subjects were also categorized with regard to change in QTc from
`baseline (< 30, 30 to 60, > 60 msec). The proportion of subjects in each category was similar
`between treatment groups, except for a higher incidence in the cinacalcet group of QTcB
`increases of 30 — 60 msec at week 26 and end of study. The occurrence of an absolute QTc >
`500 msec was similar in the 2 treatment groups (7% in the cinacalcet-treated group, compared to
`' 5% in the placebo group). The occurrence of a QTc increase >. 60 msec from baseline at any time
`during the study was 11% in the cinacalcet-treated group, compared to 9% in the placebo-treated
`group. The proportion of subjects with a normal QTcB at baseline and an increase in QTcB
`beyond the upper limit of normal during the study was 36% in the cinacalcet group compared
`with 24% in the placebo group.
`
`Page 134
`
` xIl iiis g
`
`”...
`
`r
`.
`
`xJ
`
`

`

`
`-
`Placebo
`= 101
`
`_ E
`
`Week 18
`
`Increase 30-60 msec
`
`E
`
`i
`
`n/Nl %
`
`37/76 49
`22/76 2.9
`15/ 76 20
`
`Cmacalcet
`= 291
`
`n/Nl %
`
`87/226 38
`73/226 32
`52/226 23
`
`g
`
`2/ 76 (3)
`
`36/ 73 49)
`
`'
`
`Increase >60 msec .___
`*Week 26
`Decrease
`Increase < 30 msec
`
`.
`
`
`
`14/226Q)
`__
`80/212 38
`5
`68/212 32
`,
`
`7/ 73 (10)
`I
`49/212 (23)
`Increase 30-60 msec
`6/ 73 8
`E
`l5/2l2 7
`Increase > 60 msec
`
`End of Study
`E
`Decrease
`
`l
`
`E
`
`105/258 41
`
`82/258 _(3_2)
`,:__
`28/ 8892)
`Increase < 30 msec
`__ 1ncre§§§§9:§0_msec ______ ___-.__._9_/_8§,U_0)___.._,_E_.,__._.5§_/Z_5§_2(_1)____
`
`__I_r_)crease > 60 m_sec _
`_
`u u
`__ 7/ 88Q)
`16/258 19)
`Maximum Durin Stud
`
`__
`‘_
`Decrease
`Increase < 30 msec
`
`32/ 88 (36)”
`
`“E______ 75/258 (29)
`86/258 33
`
`Increase 30-60 msec
`Increase > 60 msec
`
`_
`
`17/ 88 (19)
`8/ 88 9
`
`E
`E
`
`69/258 (27)
`28/258 11
`
`COMMENT: It is well known that there is QT interval prolongation associated with
`decreases in serum calcium levels which may be the etiology of the increased QT intervals
`seen in this study. It is not clear if there is an additional direct effect from the drug itself.
`
`Safety Conclusions: Three hundred ninety-two subjects (291 cinacalcet, 101'placebo)
`received study drug and were evaluable for safety. Deaths occurred in five subjects (3
`placebo-treated and 2 cinacalcet-treated subjects). Causes of death were consistent causes
`of death in the general population of patients with ESRD. Serious adverse events were
`reported by 26% placebo-treated subjects and. 27% cinacalcet-treated subjects were
`similar between the groups. The proportion of subjects who withdrew from the study due
`to adverse events was slightly higher in the cinacalcet group than the placebo group (13%
`in the cinacalcet group and 8% in the placebo grOup.‘ Ninety-one percent of subjects in the ’
`cinacalcet group and 93% of subjects in the placebo group reported at least 1 adverse event
`during the study. The most common adverse events were nausea, diarrhea, vomiting, upper
`respiratory infection, headache, myalgia, and abdominal pain. The gastrointestinal adverse
`events, namely nausea and vomiting were significantly higher in cinacalcet-treated
`subjects.
`
`Three (1%) subjects in the cinacalcet group and no subjects. in the placebo group
`discontinued the study because of convulsions. It is not clear if the seizures are solely due to
`change in calcium concentration. Other possible etiologies include cytochrome p450
`enzyme induction causing a decrease in anti-seizure medication levels and a direct effect
`
`Page 135
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`Clinical Review Section
`
`from this highly lipophilic drug. Significant decreases in testosterone levels were seen in
`men treated with cinacalcet. Chronic renal failure is known to cause hypothalamic-
`pituitary dysfunction affecting the sex steroid axis as well as gonadal dysfunction. The
`calcium-sensing receptor has been shown to exist on anterior pituitary cells as well as in the
`testes themselves. The etiology of the decrease in serum testosterone levels with cinacalcet
`treatment is unclear.
`
`No differences, were noted between treatment groups in routine laboratory measurements.
`Studies in monkeys showed perturbations in thyroid and sex hormone (testosterone) levels.
`In this study, the majority of subjects in both treatment groups exhibited low to low-
`normal free T4 levels with normal TSH levels, which is consistent with the sick euthyroid
`profile characteristic of patients with ESRD. No subject in either group met the definition
`of hyperthyroidism or hypothyroidism during the study.
`
`Evaluation of ECGs indicated a greater prolongation in the QTc interval in cinacalcet-
`treated subjects compared with placebo subjects. It is unclear if the increase in QT
`interval is solely related to change in calcium level or if there is "an independent drug effect.
`The incidence of QTc prolongation > 60 msec or an absolute QTcB > 500 msec was similar
`between treatment groups. This effect may be solely due to the decreases in serum calcium
`levels, although it is not clear if there is an additional direct effect from the drug itself.-
`
`Discussion and Conclusions: Current therapy for secondary HPT includes pharmacologic
`doses of vitamin D and large oral doses of calcium-containing phosphate binders. Such
`therapy is often limited by elevations in Ca x P, which have been associated with a variety
`of adverse outcomes, including increased risk of cardiac, visceral, and vascular
`calcifications. The proportion of subjects who achieved a target iPTH S 250 pg/mL was
`significantly greater in the cinacalcet group than in the placebo group (35% versus 6%; p <
`0.001). As well, a significantly greater proportion of subjects in the cinacalcet group (59%)
`compared with the placebo group (10%) had a 2 30% reduction in iPTH'(nominal p <
`0.001). Mean iPTH concentration was decreased by 40% in the cinacalcet group,
`compared with an increase of 4% in the placebo group (nominal p < 0.001). Consistent
`« reductions in iPTH were observed regardless of baseline iPTH stratum or dialysis
`- modality. The effects of cinacalcet on iPTH were independentof vitamin D sterol use or
`dose changes, indicating that cinacalcet can be used as a primary intervention or as part of ‘
`combined therapy with vitamin D sterols to control secondary HPT. At the end of study
`(week 26), subjects were distributed across all dose levels of cinacalcet, with 41% of
`subjects receiving 180 mg. Reductions in iPTH levels were accompanied by significant
`decreases in serum Ca x P, calcium, and phosphorus. Mean Ca x P in the cinacalcet group
`was reduced by 13% during the efficacy-assessment phase compared with a 1% decrease in
`the placebo group (nominal p < 0.001).
`‘
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`Clinical Review Section
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`Current K/DOQI guidelines11 list the target range ofiPTH1n dialysis patients as 150— 300
`pg/mL and a mean Ca x P < 55 (mg/dL)’. A post-hoe analysis was performed to analyze the
`proportion of subjects achieving these guideline targets. This analysis showed that 35% of
`cinacalcet subjects and 6% of placebo subjects met target goals. These results suggest that
`new therapeutic strategies using cinacalcet will assist in achieving the more stringent
`treatment goals that will be recommended for managing secondary HPT (NKF-K/DOQI).
`
`Gastrointestinal adverse events are common side effects of cinacalcet use. An unanticipated
`decrease'1n testosterone levels1n cinacalcet-treated subjects was observed. This effect1s
`thought to possibly be related to a direct drug effect, though itIS unclear if the effect1s
`- central or at the level of the testes. As well, an increase in the occurrence of seizures was
`also observed with cinacalcet treatment. Decreases in serum calcium levels may be the
`cause of the increase in seizure activity. Lower calcium levels may also be the cause of the
`QTc interval prolongation seen. With both the seizure activity and the QT effect, it has not
`been clearly determined if there is direct effects of the drug.
`Study 20010141: A Multicenter, Randomized, Placebo-controlled, Double-blind, 12-month
`Study to Assess the Effects ofan Oral Calcimimetic Agent (AMG 073) on Renal Osteodystrophy
`in Hemodialysis Patients with Secondary Hyperparathyroidism
`
`This 52-week, multicenter, randomized, double-blind study was designed to evaluate the effects
`of cinacalcet on renal osteodystrophy (metabolic bone disease) in hemodialysis patients with
`secondary hyperparathyroidism
`
`Objectives: The primary objective of this study was to evaluate the effects of cinacalcet
`compared with placebo on renal osteodystrophy as assessed by bone histomorphometry
`
`Study Design: This was a randomized, double-blind, placebo-controlled, multicenter, 12 month
`study. Seventeen centers in the United States and Europe participated in the study. Afier a 30-
`day screening period, subjects with end stage renal disease who qualified for the study were
`randomized in a 2:1 ratio to cinacalcet or placebo. Throughout the study, investigators could ‘
`prescribe concomitant therapy considered necessary
`
`The study consisted of 3 phases (see figure below): a'30—day screening phase, a 24-week dose-
`titration phase (visits every other week), and a 28-week maintenance phase (visits every 4
`weeks). Eligible subjects were randomized (2: 1) to receive cinacalcet or placebo and began
`treatment with 30 mg study drug once daily. No baseline stratification factors were used. During
`‘ the titration phase, sequential dose increases occurred every 4 weeks based on iPTH response,
`serum calcium values, and safety monitoring. Possible sequential daily doses were 30,50, 70,90,
`120, and 180 mg of cinacalcet or placebo. Dose changes also were permitted during the
`maintenance phase.
`
`” K/DOQI Clinical Practice Guidelines for Bone Metabolism and Disease in Chronic Kidney Disease. Am J Kidney
`Dis 2003, Oct. 42 (4) Supplement 3.
`
`Page 137
`
`

`

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`
`1593mm:
`0‘“
`WWW ,
`
`mm“
`in!”
`“1&le
`
`Clinical’Review Section
`
`M
`(SM
`
`ZO*-i>N—30023'23
`
`Population: The study population consisted of subjects with end stage renal disease on
`maintenance hemodialysis,
`
`Inclusion Criteria
`
`. 0
`
`0‘ > 18 years of age at the start of screening
`0 Agreed to use, in the opinion of the principal investigator, highly effective contraceptive
`measures throughout the study (both men’and women). All subjects were to notify the
`principal investigator if they or their partner suspected a pregnancy
`iPTH determination of Z 300 pg/mLi(3 l .8 pmol/L) obtained within the 30 day screening
`period
`0 Met the following criteria (central laboratory) taken within 30 days before day 1 and
`'
`before dialysis (abnormal tests could be repeated once at the discretion of the
`‘
`investigator):
`0 Serum calcium > 8.4 mg/dL (2.1 mmol/L) reported as a corrected value by the
`central laboratory
`-
`o Hemoglobin (Hb).> 9 g/dL or hematocrit (Hct) > 27%.
`In—center hemodialysis for 2 1 month before day l.
`o
`o Able to comprehend and willing to give written informed consent for participation in the
`study before any study-specific procedures were performed.
`
`Page 138
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`Clinical Review Section
`
`Exclusion Criteria
`
`Had an unstable medical condition, defined as having been hospitalized within 30 days
`before day 1, or were otherwise unstable in the judgment of the investigator
`Pregnant or breastfeeding
`'
`Parathyroidectomy1n the previous 6 months
`Received vitamin D sterol therapy for < 30 days before day l or required a change in
`vitamin D sterol brand or deselevel within 30 days before day l (for subjects prescribed
`vitamin D sterols).
`Received, within 21 days before day 1, therapy with flecainide, systemic glucocorticoids
`(> 5 mg/day, prednisone equivalent), lithium, thioridazine, haloperidol, calcitonin, or
`, tricyclic antidepressants ..(eg.., imipramine, desipramine). (The tricyclic antidepressant
`amitriptyline1s permitted.)
`Received within 90 days before day 1, therapy with bisphosphonates or fluoride.
`(Unchanged doses of estrogen [> 1 year] or thyroid replacement therapy [2 3 months]
`were permitted.)
`Known to abuse alcohol, or use illicit drugs, within 12 months before day l.
`Myocardial infarction (MI) within 6 months