CENTER FOR DRUG EVALUATION AND
`-
`- RESEARCH '
`‘
`
`'
`
`APPLICA TI0N NUMBER:
`21-688
`
`.
`
`STATISTICAL REVIEW! S!
`
`

`

` US. Department of Health and Human Services
`
`Food and Drug Administration
`Center for Drug Evaluation and Research
`Office of Pharmacoepidemiology and Statistical Science
`Office of Biostatistics
`
`STATISTICAL REVIEW AND EVALUATION
`CLINICAL STUDIES
`
`NDA/Serial Number:
`
`21-688
`
`Drug Name:
`
`Indication(s):
`
`SENSIPAR (cinacalcet HCI)
`
`
`treatment of secondary hyperparathymidismin patients with
`Chronic Kidney Disease, receiving or not receiving dialysis.
`
`Treatment of hypercalcemiain patients with parathyroid carcinoma, or in patients
`with primary hyperparathyroidism for whom parathyroidectomy is not a treatment
`option.
`
`Applicant:
`
`Date(s):
`
`Amgen
`
`Submitted 9/5/03. PDUFA due date 3/8/04
`
`Review Priority:
`
`Priority
`
`Biometrics Division:
`
`Division of Biometrics 2 (RFD-715)
`
`Statistical Reviewer: _
`Concurring Reviewers:
`
`Joy Mere, MS.
`
`Todd Sahlroot, Ph.D. (Team Leader)
`Ed Nevins, PhD. (Division Director)
`
`Medical Division:
`
`Clinical Team:
`
`Division of Metabolic and Endocrine Drug Products (RFD-5 10)
`Theresa Kehoe, MD (Medical Reviewer)
`’
`Patricia Beaston, MD. (Medical Reviewer)
`
`Project Manager:
`
`Eric Colman, M.D. (Team Leader)
`
`David Orlotf, MD. (Division Director)
`Randy Hedin
`I
`
`Keywords: NDA review, Clinical studies, Safety analyses
`
`

`

`1. EXECUTIVE SUMMARY OF STATISTICAL FINDINGS4
`
`1.1
`
`Conclusions and Recommendations............................................................_................................................ 4
`
`1.2 Brief Overview of Clinical Studies.................................................................... 7
`
`................................. 7
`1.2.1 Primary Hyperparathyroidism
`1.2.2 Secondary Hyperparathyroidism ................................................................................................................ 7
`
`1.3 '
`
`Statistical lssues.................................. 10
`
`2.
`
`INTRODUCTION .......
`
`.......
`
`...............
`
`.................. 11
`
`2.1
`
`2.2
`
`Overview ................................................................................................................................................ 11
`
`Data Sources ............................................................................................................................................ 1 l
`
`3. STATISTICAL EVALUATION .............................. . .......
`
`................................... 1 1
`
`3.1
`
`Evaluation of Efficacy ...................................................................................................................... 11
`3.1.] Primary Hyperphosphotemia......................................................................................................................... 11
`3.1.2 Secondary Hyperphosphotemia in Patients with End Stage Renal Disease................................................... 18
`3.1.2.1 Phase 2 Studies 990101, 990102 and 990740 ....................................................................................... 18
`3.1.2.2 Phase 3 Studies 20000172, 20000183 and 20000188 ......................................................................... 20
`Design ......................................................................................................................... ’. ....................... 20
`Sterols
`.........................................................'........................................... 2 1
`
`...................................................................................................... 22
`Patient Disposition
`Baseline Demographics....................................................................................................................... 24 '
`Dosmg......... 26
`StatisticalMethods............................ 26
`
`........................................................................................................................... 26
`Efficacy Results
`3.1.3 Secondary Hypeiphosphotemia in Patients with Chronic Renal Insufficiency.............................................. 30
`3.1.4 Extension Study 20010240 in Patients with Secondary HPT........................................................................ 36
`3.1.5 Ovérsuppression of iPTH .............................................................................................................................. 39
`3.1.6 Bio intact PTH versus intactPTH.............................................. 41
`
`3.2
`
`Evaluation of Safety ....;.,........‘........2...”...........................................;;.......’.....................“............‘... 43
`
`4. FINDINGS IN SPECIALISUBGROUP POPULATIONS44
`
`4.1 Gender, Race and Age...................... 44
`
`4.2 Subgroup Populations Defined by Baseline Characteristics ............................ 44
`
`5. SUMMARY AND CONCLUSIONS ........................................................................... 46
`
`5.1 Conclusions and Recommendations ........................................................................... 46
`
`5.2 Labeling recommendations and comments............................. 49
`2
`
`

`

`Appendix 1. Study 20000159 calcium and daily dose graphed by patient ......”..;................................................ 50
`
`Appendix 2. Study 20000204 calcium and daily dose graphed by patient ......m........ 53
`
`Appendix 3. Histogram and cumulative distribution plots of baseline iPTH (pg/mL) by protocol ................. 54
`
`Appendix 4. iP'l‘H (pg/mL) by week for Study 183 with reference lines at 250, 150 and 100 pg/mL-.............. 55
`
`Appendix 5. iPTH (pg/mL) with reference lines at 250, 150 and 100 pg/mL by original protocol and by week
`for Extension Study 240
`........................................"‘""”""."............................................................... 56
`
`Appendix 6. Number of times iPTH (pg/mL) under 100 or 150 pg/mL during the last 6 visits on study (Weeks
`16-26) for Studies 172,183 and 188 combined ............ ............ ...”............................................. 57
`
`

`

`1 . EXECUTIVE SUMMARY OF STATISTICAL FINDINGS
`
`1.1
`
`Conclusions and Recommendations
`
`The applicant’s proposed indications for cinacalcet (sensipar) are the following:
`
`0 Treatment of hypercalcemia in patients with primary hyperparathyroidism or with parathyroid
`‘ carcinoma
`
`Treatment of secondary hyperparathyroidism
`Control of parathyroid hormone (PTH), serum calcium-x phosphorus, phosphorus and
`calcium levels in patients with chronic kidney disease receiving or not receiving dialysis
`
`Vifith regard to primary hyperparathyroidism, this reviewer has the following comments and
`conclusions based on this statistical review:
`‘
`
`
`
`
`% . No assessment of
`safety can be made“ iust based on 990120 since clearly patients with serious ADE’s in ‘
`980125 would not continue into 990120.
`‘
`
`NJ
`
`e arath roidism in atients with ESRD and receivin dial sis, this
`h
`With regard to seconda
`reviewer has the following comments and conclusions based on this statistical review:
`
`, . Three Phase 2 studies showed that doses above 50 mg per day are usually needed to
`significantly impact PTH particularly in patients with baseline PTH above about 525.
`In the three large Phase 3 studies (172, 183 and 188), about 39% had mild HPT
`
`o
`
`

`

`I»
`
`(300<iPTHs500), about 35% had moderate HPT (500<iPTH<800) and about 27% had
`severe HPT (iPTH>800).
`Two to three times more cinacalcet patients dropped out of the Phase 3 studies due to
`gastrointestinal ADE's than placebo patients (see Table 17). The dropout rate in the
`European study (183) was considerably higher (14% cinacalcet vs. 2% placebo).
`Gastrointestinal ADE was also the major reason for cinacalcet dropoutsIn the extension
`study.
`« The median cinacalcet dose was 90 mg. A little more than 1/3 of the randomized cinacalcet
`patients were on the highest dose at the end of their treatment. Titration to the highest dose
`of180 mg was related to baseline iPTH; about 60% of patientsIn the highest baseline iPTH
`tertile were titrated to the 180 mg dose.
`Cinacalcet significantly decreased iPTH by about 50% over placebo About half the patients
`had a decrease of 30% or more
`
`About 40% of patients treated with cinacalcet had mean iPTH during maintenance lower
`than 250 pglml (the primary endpoint) compared to about 5% for placebo; about half of the
`cinacalcet patients were below the normal range (<150 pglml, Table 20).
`Cinacalcet significantly lowered calcium, phosphorus and Ca x P compared to placebo
`(Table 21) ChangesIn these endpoints were not correlated with changesIn the primary
`-
`endpoint iPTH.
`A double-blind extension study (240) of a total of 266 patients from Study 172 (about 52% of
`the randomized patients) and from Study 183 (about 15% of the randomized patients)
`followed patients for an additional 26 weeks (total of one year). Less than one-third of the
`randomized patients from those studies completed the extension.
`Nearly half of the patients in the extension study required the highest dose of 180 mg per
`day to adequately lower iPTH.
`In the 3 phase three trials, about 1/5 of the patients had a mean iPTH below 150 pglmL (the
`target range, was 150 to 250); about half of those patients (~10% of the total) had levels
`below 100 pglmL. In the applicant's bone study, two' patients who developed adynamic bone
`disease had iPTH levels below 100; a preliminary review indicates that only two patientsIn
`that study had an iPTH below 100 (this reviewer will confirm this after completion of this
`document).
`.»
`Patients with high levels of iPTH (>800 for secondary HPT, ESRD patients) are not able to
`achieve levels of 250 or less even on the highest dose; the median iPTH for this subgroup
`during the efficacy phase was 703 pglmL for cinacalcet and 1160 for placebo.
`‘
`
`WIth regard to secondary hypergarathfloidism in pgients with CRI and not receiving dialfiis,
`this reviewer hasthe following comments and conclusions based on this statistical review:
`
`(EM
`
`

`

`~
`
`Given that HPT'Is a chronic disease requiring chronic treatment, itIs important to look at the
`number of patients maintained on treatment'In the extension studies. In Study 20010240 (an
`extension of Studies 172 and 183In secondary HPT patients), only 28% (n=210, 97 on
`cinacalcet) of the originally randomized patients completed the 26-week extension study. Two
`additional extension studies were conducted, Studies 20000130 and 20020158. Study
`20020158 is ongoing «and data from this study were not provided in the NDA. Study 2000130
`enrolled 170 patients from the Phase 2 studies and Study 237. After 1 year of treatment, 117
`patients were on study; about 40% had an iPTH value less than 250 pg/dL. So the data for
`secondary HPT patients one year and beyond is limited in the application, although the applicant
`continues to treat patients in 20020158 which should provide a much larger database of patients
`treated long-term. r
`
`
`,”
`
`aMM
`
`J
`
`The clinical trials provide statistical evidence of the efficacy of cinacalcet for the treatment of
`/*—-'—~ secondary HPT. Two problems with the efficacy are evident: 1) most
`secondary HPT patients with high levels of iPTH and parathyroid carcinoma patients with high
`levels of calcium are not able to achieve normal levels so dosing does not appear to be sufficient
`for patients with severe disease and 2) about half the responders reach levels below the target
`range of iPTH. Oversuppression of iPTH can lead to detrimental effects on bone. In addition. the
`benefits need to be weighed against risks which may include hypocalcemia, QT interval
`prolongation. changes in testosterone levels and seizure.
`
`APPEARS THIS WAT .
`0" ORIGINAL
`
`

`

`1.2 Brief Overview of Clinical Studies
`,
`The applicant has submitted the results of 25 Phase 2 and Phase 3 clinical tn‘als designed to
`demonstrate the efficacy and safety of cinacalcet for the treatment of primary and secondary
`’ hyperparathyroidism (HPT); these trials are briefly described in the following two sections of this
`reVIew.
`.
`
`1 ..2 1 Primary Hyperparathyroidism
`
`»
`
`For patients with primary HPT the applicantIs seeking an indication for the treatment of
`
`hypercalcemia. C,__
`_
`,
`‘
`, _ ..
`
`.
`..
`
`,3
`
`,
`
`.
`
`Three studies (980125, 990120 and 990160), designed to study primary HPT in patients with
`above normal iPTH and above normal semm calcium (Table 1), were placebo-controlled
`studies. Study 980125 was primarily a PK study but also provided some efficacy data. In Studies
`980125 and 990120. titration studies, the highest dose administered was 50 mg BID. In Study
`990160, a higher dose of 65 mg BlD was studied.
`
`V
`
`
`
`A
`
`1.2.2 Secondary Hyperparathyroidism
`
`The applicant studied the effects of cinacalcet'In two populations of patients with secondary
`HPT; end-stage renal disease (ESRD) patients on dialysis and chronic renal insufficiency (CRI)
`patients not on dialysis.
`
`7
`
`

`

`The results of 8 placebo-controlled clinical trials were submitted to support a secondary HPT
`indication in patients with ESRD (Table 2); all patients were receiving dialysis. In all trials the
`= entry criterionfor iPTH at baseline was.300 pglmL or greater.
`In three Phase 2 trials, 990101,
`990102 and 990740, it was determined that doses up
`100 mg daily were not sufficient and so
`subsequent trials (20000172 20000183 and 200018 ) used doses up to 1.80 mg daily; these
`latter three trials are considered the pivotal trials in ESRD patients and therefore receive the
`most attention in this review. Study 20000237 was similar in design to the 3 large trials and is not
`reviewed here due to its small size (82 patients) and short treatment period (12 weeks). Two
`studies (990126 and 20010141) were designed to examine effects on bone and are not
`reviewed here (see the review of medical reviewer, Dr. Theresa Kehoe, for further details).
`
`Cinacaloet Dosing
`Once Dail
`
`Treatment Periods
`
`
`
`Table 2. Randomized, double—blind, placebo-controlled studies in patients with secondary HPT as a
`co
`- ouenoe of end-sta-e renal disease ESRD
`'
`
`
`Treatment
`Primary
`
`
`
`- rou cs
`End . cint
`
`
`Cinacaloet (39)
`% of pts.
`Trtration: 12 wks
`Start 20 mg
`
`
`Placebo (39)
`with iPTH %
`Trtrate to 10, 30, 40 Maintenance:6 wks
`
`Hemodialysis 23
`
`
`
`mos.
`ch230%
`and 50 mg
`Follow-up: 36 wks
`
`
`
`
`Trtration: 12 wks
`
` BONE
`
`
`
`
`iPTH2500 pglmL
`Cinawlcet (9)
`Substudy
`990101 pts with
`Start 20 m9
`
`Trtrate to 10, 30. 4O Maintenance:6 wks
`Placebo (6)
`
`990126
`
`
`
`
`and 50 m
`Follow-u : 36 wks
`
`
`
`
`
`
`
`
`% of pts.
`Start 20 mg
`Titration: 12 wks
`Cinacaloet (31)
`iPTH2300 pglmL
`
`
`
`with iPTH %
`Trtrate to 10, 30, 40
`(open label; rand.
`Placebo (31)
`Hemodialysis
`
`
`
`
`and 50 mg _
`after titration)
`ch230%
`
`
`y
`Maintenance:9 wks
`
`Follow-u : 32 wks
`
`
`iPTH2300 pglmL . Cinacaloet (36)
`Hemodialysis 23
`Placebo (35)
`mos,
`rit. D
`
`Start 25 mg
`Trtrate mm, 75 and
`100 mg
`
`990740 »
`
`20000172
`
`20000183
`
`
`
`
`
`
`
`% of pts.
`Titration: 12 wks
`with iPTH %
`Maintenance:6 wks
`
`
`d123O%
`Follow-up: 36 wks
`% pts. with
`Titration: 12 wks
`
`
`Cinacaloet
`Start 30 mg
`iPTH2300 pglmL
`
`iPTH5250
`Maintenancez14 wks
`(205)
`Trtrate 10 60. 90. 120
`Hemodialysis 23
`
`
`pglmL
`Placebo,(205)
`and 180 mg
`mos.
`
`
`
`
`
`‘
`’
`Corrected ser.
`
`
`
`
`Cinacaloet
`
`Trtration: 12 wks
`
`
`Start 30 mg
`
`
`Maintenance214 wks
`Trtrate to 60, 90, 120
`(166)
`Hemodialysis 23 '
`
`
`
`
`mos.
`'
`and 180 mg
`Placebo (165)
`
`
`
`
`Titration: 16 wks
`
`
`
`Start 30 mg '
`.
`
`
`
`‘ Maintenance:10 wks
`Trtrate to 60, 90, 120
`pglmL
`
`
`
`
`
`Placebo (1 01)
`and 180 mg
`.
`Hemodialysis or
`
`
`
`
`
`peritoneal dialysis
`
`
`
`
`
`21 mo.
`.
`
`
`
`
`Titration: 8 wks
`Mean iPTH2300
`Start 50 mg
`
`Cinacaloet (41)
`
`Maintenance:4 wks
`
`
`Trtrate to 70, 90, 120
`Placebo (41)
`pglmL
`
`and 180 mg
`Hemodialysis 23
`
`
`
`mos.
`
`20010141
`iPTH2300 pglmL
`Cinamlcet (32)
`Start 30 mg
`Titration: 24 wks
`
`
`Hemodialysis
`Placebo (16)
`Trtrate to 50, 70. 90, Maintenance:28 wks
`
`21 mo.
`120 and 180 mg
`
`

`

`Two studies were conducted in patients with secondary HPT as a consequence of CRI (Table
`3); these patients were not receiving dialysis These two trials (2000236 and 20010239) differed
`on entry criteria, titration schemes and primary endpoints. Theresults from 236 were used to
`design 239. Both trials are reviewed here.
`
`‘
`
`‘ studies in patients with secondary HPT
`
`Primary
`
`Patients completing double-blind treatment in one of the aforementioned studies could continue
`treatment in one of the extension studies listed in Table 4. Only Study 20010240 is reviewed in
`any detail here. This study was an extension of Studies 172 and 183; patients remained on .
`
`randomized treatment'in this study and the study retained the double-blind for 26 weeks.
`
`20010240
`, double-blind
`'
`P aoebo-controlled
`
`
`
`20000172 + 20000183
`:
`.
`
`
`
`
`Treatment periods
`
`
`
`Table-4. Extension studies in oatients with secOnda HPT
`Extension Study
`Source Studies
`' Cinacaloet Doses +
`Sam - le Size
`
`
`
`Start 30 mg
`,
`Maintenance: 26 wks
`
`
`Trtrate to 60, 90, 120 and
`‘
`180' mg
`
`N=128 cinacaloet
`N.==138 . Iacebo
`Start 30 mg
`Trtrate to 50, 70/75,
`90/100,120 and 180 mg
`N=170
`
`
`
`
`20000130
`open-label
`
`
`
`
`990101, 990102, 990740
`+20000237
`
`Titration: 12 wks
`Maintenance: up to 4 years
`
`
`
`20000236
`
`Start 30 mg
`20010142
`Titration: 10 wks
`Titrate to 60, 90, and 120
`open-label
`Maintenance:100 wks planned
`
`
`Start 30 mg
`20000172, 20000183,
`20020158
`Titrate to 60. 90. 120 and
`20000188, 20010141 ,
`open-label
`
`
`18° "‘9
`+2001
`4
`
`02 0
`N=563 still enrollin
`
`
`
`

`

`1.3
`
`Statistical Issues
`
`There were no issues regarding the statistical methods used that impacted the interpretation of
`
`the efficacy results.
`
`Some of the issues examined by the reviewer but’not discussed in detail in the body of the
`review were:
`
`0 The Sensitivity analyses performed by the applicant.
`0 There were several instances where problems with the PTH assay resulted in
`rerunning the assays. This reviewer found no impact on the efficacy results.
`0 Analyses of LOCF data were consistent with completer analyses
`0 Averaging of the maintenance values
`.
`For each study, this reviewer looked at the by-week results to be sure that
`these results were consistent with the results of the primary analysis of the
`averaged values.
`. Normality of the data
`. When the data was found to depart from normality, nonparametric analyses
`were performed by the reviewer (e.g. testosterone)
`Impact of dropouts
`. Dropouts were not a major issue with, usually, more than 80% of the patients
`providing data for the efficacy analyses.
`. A difference between reasons for dropout for European and US studies was
`examined carefully by this reviewer. ,
`
`.
`
`Due to the complexity of this review and the shortened review time , there were a number of
`If
`issues that arose at the end of the review process that could not be addressed'in this review.
`this reviewerIfinds with further review that theseIssuesshould be documented, an addendum to
`this review will be created.
`'
`
`APPEARS THIS WAY
`0N ORIGINAL
`
`10
`
`

`

`2.
`
`Introduction
`
`2.1
`
`Overview
`
`Cinacalcet a calcimimetic, regulates "plasma PTH secretion by amplifying the receptors
`sensitivity to extracellular calcium and thereby reducing PTH concentrations” (page 36 of the
`applicant’s clinical report of Study 172).
`in addition to controlling iPTH levels, cinacalcetIs
`intended to control phosphorus and calcium levels Levels of phosphorus greater than 6.5
`mgIdL and/or of Ca x P greater than 72 (mgldL)2 elevate the risk of deathIn dialysis patients.
`
`The applicant is seeking indications for both primary and secondary HPT. Forprimary HPT; the
`database presented here is small. Most of the application consists of data from patients with
`secondary HPT so most of this review is focussed on secondary HPT. See Tables 1 through 4 in
`the previous section of this review for a summary of the clinical trials provided in the NDA for
`cinacalcet.
`
`The primary goal of cinacalcet therapy in patients with secondary HPT is to control levels of
`iPTH, Ca x P, Ca andg‘P reaching the target values shOWn in Table 5 (from the NDA). In most of
`the secondary HPT trials in this submission, the primary endpoint was percentage of patients
`reaching an iPTH level of 250 pglmL. Measures of effect on Ca, P and Ca x P were included as
`secondary endpoints.
`
`
`
`Table 5. Tar-et values for seconda HPT Metabolic carameters in ESRD
`
`_
`
`
`
`
`
`
`
`[imm- 3555 mIdL
`
`
`
`2.2
`
`Data Sources
`
`Datesets and study reports were accessible from the CDER Electronic Document Room at
`\\CDSESUB1\N2 1 68 8 \N 000\2003— 09— 05. Hardcopies of study reports for studies
`"selected by this reviewer were reviewed also.
`
`All graphs and tables were created by thereviewer unless othenrvise noted. Also results
`presented in tables, were calculated by the reviewer unless othenrvise noted.
`
`3. Statistical Evaluation
`
`Evaluation of Efficacy
`3.1
`3.1.1 Primary Hyperphosphotemia
`
`

`

`.u‘J—v
`
`' 4? page(s) have been
`' removed because it
`.c‘0ntains trade secret *
`
`‘
`
`*
`
`‘
`
`and/or confidential
`information thatIS not
`diselosable
`
`

`

`
`
`fif—\
`
`3.1.2 Secondary Hyperphosphotemia in Patients with End Stage Renal Disease
`
`' 73.1.2.1 Phase 2 Studies 990101.990102' and 990740
`
`The applicant conducted three Phase 2 studies (990101, 990102 and 990740) in patients with'
`secondary HPT as a consequence of ESRD (Table 10). The to-be-marketed formulation for
`sensipar was _r_1_o_t used in these studies. The inclusion criteria (Table 11) were essentially the
`same for the three studies. Patients were excluded if they had'a parathyroidectomy within six
`months, had received an investagational drug within 28 days, had a seizure within 12 months or
`had a gastrointestinal disorder with impaired absorption.
`0
`
`In the first studies conducted (101 and 102), patients were titrated to a maximum dose of 50 mg;
`in the third Phase 2 study (740), patients could be titrated to a maximum of 100 mg per day. In
`all studies the primary outcome variable was proportion of patients with a percent change from
`
`18
`
`

`

`baseline of 30% or more during a maintenance phase.
`
`Table 11. Seconda HPT in oatients with e‘nd-sta- e renal disease ESRD : Phase 2 studies
`
`Study
`Entry Criteria
`Treatment
`Cinaeaieet Dosing
`Treatment Periods
`. rou -s
`Once Dai
`
`
`
`
`
`
`End - int
`
`
`
`
`
`
`
`
`iPTH2300 pglmL
`990101 -
`Titration: 12 wks
`Start 20 mg
`Cinacalcet (39)
`(US and
`Hemodialysis 23
`Titrate to 10. 30, 40 Maintenance:6 wks
`Placebo (39)
`
`
`
`Canada)
`mos.
`and 50 mg
`Follow-up: 36 wks
`
`
`
`
`990101ptswith
`Substudy
`Start 20 mg
`Titration: 12 wks
`
`Titrate to 10, 30, 40 Maintenance:6 wks
`990126
`iPTHzSOO pg/mL
`
`
`
`Follow-u -: 36 wks
`and 50 m
`
`
`
`
`
`
`Cinacalcet (31)
`Start 20 mg
`Titration: 12 wks
`
`
`
`Placebo (31)
`Tttrate to 10, 30, 40
`(ogn label
`
`
`
`
`
`cin cal
`-
`and 50 mg
`
`
`mm
`
`mm
`
`Maintenancec9'wks
`
`
`
`Follow-u .; 32 wks
`% of pts.
`iPTHZSOO ngmL
`Cinacalcet (36)
`Titration: 12 wks
`Start 25 mg
`
`with iPTH %
`Hemodialysis 23
`Placebo (35)
`Titrate to 50. 75 and Maintenance:6 wks
`
`(3.230%
`mos.
`rit. D
`100 mg
`Follow-up: 36 wks
`
`Cinacalcet (9)
`
`Placebo (6)
`
`
`
`
`iPTH2300 pglmL
`Hemodialysis
`
`
`
`990740
`(US)
`
`In Studies 101 and 102 about 85% of the patients completed the maintenance phase while
`retention was a little higher in Study 740 at 92 %.
`
`About 60% of the patients in Studies 101 and 102 were titrated to 50 mg per day; about 47% '
`were titrated to 100 mg in Study 740 with another 22% titrated to 75 mg.
`
`APPEARS TlllS WAY
`on ORIGINAL
`
`19
`
`

`

`The iPTH results for the Phase 2 studies are summarized'in Table 12 below. WIthin each study,
`treatment groups are comparable for iPTH at baseline though considerable variability is evident
`in each group. The treatment effects on iPTH are summarized by this reviewer using three
`different endpoints; proportion of patients with iPTH of 250 or less (a primary endpoint in the
`Phase 3 studies), proportion of patients with decrease in iPTH % change from baseline of 30%
`or more (the primary endpointIn these studies) and the mean % change from baseline. The
`results for Study 990740 show statistically significant treatment effects for all three endpoints
`and generally larger effects than those observedIn Studies 990101 and 990102‘. The results
`from these studies demonstrate that closes higher than 50 mg are needed to obtain significant
`lowerin ' this reviewer found this to be articularl
`true for atients with basel'ne values of iPTH
`
`above about 525 pglml.
`
`Table 12. Secondary HPT in patients with ESRD: Phase 2 Studies
`. . licant’s iPTH results durin- the maintenance ohase
`
`
` — Study 990101 S_udy—9o1oz
`
`p-
`
`value
`
`Cin/Pla
`
`n=31
`
`n=31
`
`“'03
`
`n=35
`
`n=36
`
`value
`
`- Placebo
`
`
`
`n=39
`
`637 (456)
`494
`
`n=39
`
`632 (280)
`607
`
`Baseline
`
`Mean (SD)
`Median
`% of pts WI
`
`
`CinlCin -—Placebo Cinacal P-
`
`
`
`
`600 (271)
`496
`
`680 (298)
`598
`
`583 (421)626 (311)
`461
`579
`
`
`00 mL
`% of pts wl
`
`iPTH %ch
`230% Dec
`
`iPTH %ch
`-32% (44)
`+3% (47)
`Mean (SD)
`+22% (38)
`-26% (29)
`—2% (37)
`-13% (40)
`
`49%
`+2%
`Median
`+25%
`-23%
`-2.4%
`-17%
`
`' P-value results from stratified CMH to test proportions and from ANOVA to test continuous variables.
`
`8%
`
`38%
`
`0-001
`
`23%
`
`35%
`
`23%
`
`53%
`
`
`
`
`
`
`3.1.2.2 Phase 3 Studies 20000172, 20000183 and 20000188
`
`Design
`
`Studies 20000172 (referred henceforth as Study 172), 20000183 (183) and 20000188 (188)
`were multicenter, double-blind, randomized, controlled, Phase 3 clinical trials designed to
`assess the'efficacy and safety of cinawlcet compared to placebo in patients with uncontrolled
`secondary hyperphosphotemia as a consequence of end-stage renal disease and on dialysis;
`
`In all three studies, treatment (cinacalcet or placebo) was titrated from 30—>60—'>90——)120—>180
`mg, once daily, dependent on the patient’s iPTH level (iPTH>200 pg/mL with serum C8278)
`and safety endpoints. Cinacalcet was titrated to the next higher dose during the titration phase
`unless the iPTH was 200 or less, or the serum calcium was less than 7.8 or for an ADE.
`
`In Studies 172 and 183, stratified randomization was 1:1 while for Study 188 the ratio was 3:1. ,
`For Studies 172 and 183, randomization to Cinacalcet or placebo was stratified on baseline
`‘iPTH and Ca x P based on 3 levels of iPTH (3OOSiPTHSSOO, 500<iPTH$800 and iPTH>800)
`
`1 The results for Study 102 are clearty weak. Given the results, the unusual ADE rate and the design of switching
`from cinawlcet to randomized treatment, this reviewer questions whether there were more protowl violations than
`the few that were reported. Since this is a small Phase 2 trial, it does not deserve further reviewer scrutiny.
`
`2 0
`
`

`

`a
`
`and 2 levels of Ca x P (570 and >70). For Study 188, randomization was stratified on baseline
`iPTH and dialysis modality using four strata (300$iPTHs500 and hemodialysis; 500<iPTHsBOO
`and hemodialysis; iPTH>800 and hemodialysis; and iPTH>300 and peritoneal dialysis).
`
`Entry criteria included the following:
`. Men and women aged 18 years or older
`0 Mean of 3 (2 for Study 188) iPTH measures taken within 30 days of Day 1 2300 pglmL
`. Mean of 3 (2 for Study 188) serum calcium measures taken within 30 days of Day 1 28.4
`mgldL
`.
`3 times weekly in-center hemodialysis for 23 months before Day 1 for Studies 172 and 183;
`hemodialysis or peritoneal dialysis for 21 month before Day 1 for Study 188
`'
`o No change in vitamin D dose within 30 days prior to Day 1
`. No change in phosphate binder dose, calcium supplement dose or dialysate calcium
`- concentration within 30 days prior to Day 1 (Studies 172 and 183 only)
`
`Patients with a history of seizures were allowed in these trials; in the applicant’s Phase 2 trials of
`secondary HPT, patients with a history of seizures within the year previous to randomization
`were excluded.
`
`In all three studies, concomitant therapy with phosphatebinders and Vitamin D was allowed with
`changes to the dose levelspennitted during the trial as described in the table below.
`
`Table 13 Secondary HPT in patients with ESRD: Phase 3 Studies
`Applicant’s Table 2 describing concomitant therapy guidelines
`reformatted b reviewer
`_ so Days Before Study
`' hosphate
`! ixed dose and brand
`I: inders
`'
`
`
`
`Day 1 to End of Study
`omplete flexibility of dose and brand
`,
`
`
`
`APPEARS THIS WAY
`on ORIGINAL
`
`21
`
`

`

`All three trials consisted of thme phases (Table 14), a screening phase. titration phase and
`efficacy assessment phase. Studies 172 and 183 had identical designs while Study 188 had a
`longer titration phase by 4 weeks. All three trials were 26 weeks long.
`
`
`
`
`
`
`Table 14. Secondary HPT in patients with ESRD: Phase 3 Studies 172, 183 and 188
`Trial uhases
`
`Stud 188
`Stud 183
`Em Stud 172
`30 days ——
`
`
`Weeks 1 to 3
`Weeks 1 to 3
`Weeks 1 to 19
`
`
`
`Weekly \fisits '
`Bi-weeky Vrsits
`Weekly Visits
`
`Titrate every § weeks
`Titrate every g weeks
`Titr'ate every 4 weeks
`
`
`
`
`from 30 mg to
`from 30 mg to
`from 30 mg to
`
`
`
`maximum of 180 mg
`maximum of 180 mg
`maximum of 180 mg
`
`
`based on iPTH
`based on iPTH
`based on iPTH
`
`
`
`
`restonseand safe
`' reSunseand safe
`resunseand safe
`
`
`
`
`Weeks 17 to 26
`Weeks 13 to 26
`Weeks 13 to 26
`
`Efficacy-
`
`assessment
`1_4 weeks
`'
`. fl weeks
`
`
`
`Bi-weekly Visits
`Bi-weekly \fisits
`
`
`
`Titration allowed at
`Titration allowed at
`
`
`Weeks 16, 20 and 24
`Weeks 16 20 and 24
`
`
`
`
`
`
`
`
`fl weeks
`Bi-weekly Visits
`Titration allowed at
`Weeks 20 and 24
`
`The primary efficacy variable in all the trials was the proportion of subjects with a mean plasma
`iPTH value3250 pg/mL during the efficacy assessment phase.
`
`Secondary efficacy variables included the following:
`.
`proportion of patients with mean iPTH % decrease from baseline 230% in the efficacy phase
`. % ch from baseline in mean Ca x P during the efficacy phase
`0
`change from baseline in cognitive function by the KDQOL at end of efficacy phase
`
`Tertiary efficacy variables included the following:
`o % change in mean iPTH, mean Ca and mean P during the efficacy phase
`,, proportion of ptS with both a mean plasma iPTH value3250 pglmL and reduction from
`baseline in Ca x P during the efficacy phase »
`‘
`‘
`
`Patient Disposition
`
`Studies 172 and 188 were primarily conducted in North America with the majority of the patients
`enrolled within the United States (Table 15). Most of the patients in Study 183 were enrolled in
`European centers.
`
`Table 15. Secondary HPT in patients with ESRD: Phase 3 Studies 172, 183 and 188
`Location of centers
`.
`mm- smd 188
`__
`Europe and
`North America and
`Australia
`Australia
`
`Australia N=14
`
`Canada N=38
`US
`N=372
`
`Europe N=286
`Australia N=45
`
`Canada N=93
`US
`N=288
`
`22
`
`

`

`Jam
`
`Roughly 400 patients were randomized in each of the three trials with 1:1 assignment in Studies
`172 and 183 and 3:1 in StUdy 188 (Table 16). More than 80% of the patients in each treatment
`group completed the titration phase. About "/4 of the patients in Studies 172 and 188 (the US
`studies) completed the study.
`In the European study (183), the completion rates for the groups
`differ appreciably with only 64% of the Cinacalcet patients and 80% of the placebo patients
`completing.
`
`Table 16. Secondary HPT in patients with ESRD: Phase 3 Studies 172, 183 and 188
`Patient Disosition
`__——MII_
`———————
`
`
`
`
`—--‘---_-c-
`Titration Phase
`
`
`291 (99%)
`101 (100%)
`165 (>99%)
`165 (100%)
`200 (98%)
`204 (99+,%)
`
`
`
`
`
`
`Efficacy Phase
`
`Week 18
`
`Week 1
`Week 4
`Week 8
`Last Week1
`
`239 81%
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`158 77%
`
`146 71%
`146 71%
`
`132 80%
`132 80%
`
`107 64%
`107 64%
`
`77 76%
`77 76%
`
`294 74%
`294 74%
`
`Pts with at least
`one value in
`efficac chase
`
`174 85%
`
`.
`
`169 82%
`
`150 91%
`
`139 84%
`
`84 83%
`
`238 81%
`
`
`
`The major reason for patients discontinuing treatment in all treatment groups was the
`occurrence of an adverse event (Table 17). In Study 183 (the European study), nearly 5 times as
`many patients on cinacalcet (23%) dropped due to ADE than on placebo (5%). No significant
`treatment group difference in ADE incidence rates is seen in the two USA studies.
`
`Table 17. Secondary HPT in patients with ESRD: Phase 3 Studies 172, 183 and 188
`Reasons for discontinuation
`Stud 172
`
`
`
`n=205
`
`n-205
`
`Stud 183
`Placebo
`Cinacalcet
`n=165
`n=166
`
`Stud 188
`Placebo
`Cinacalcet
`n=101
`n=294
`
`,
`
`ADE
`
`-
`
`s
`
`
`
`
`
`
`W » Inn-nun
`
`Withdrawn
`
`Lost-tO-FU
`Death
`Parath oidectom
`Kidne translant
`
`Other
`
`5
`
`0
`
`10 5%
`12 6%
`3 2‘7
`4 2%
`1 1%
`13 4%
`“mm-.-
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`VVIthin the cinacalcet group, the majority of the ADE’s were gastrointestinal including diarrhea,
`nausea and vomiting. The incidence of these events is shown in Table 18 below. There is clearly
`
`1 Week 12 in Studies 172 and 183 and Week '16 in Study 188.
`
`2 3
`
`

`

`a marked difference in gastrointestinal event rates between the placebo and cinacalcet/groups
`with more than twice as many events in the cinacalcet group; the differenceis particularly
`significant within Study 183, the EurOpean Study.
`
`
`
`Table 18. Secondary l-lPT in patients with ESRD: Phase 3 Studies 172, 183 and 188
`Gastrointest