Clinical Safety Review
`Lourdes Villalba, M.D.
`NDA 22-253, -254.
`.— Lacosamide for the treatment of partial-onset seizures
`
`0(4)
`
`Appendix 11a. Cases of dyskinesia in partial onset seizure studies (EP Sl)
`
`Age/
`fl
`
`'
`
`
`ID
`gender
`Trtgflg
`AE term
`Action 4' Outcome _'__Relfl
`
`intermittent jerking right
`
`58 M
`75401231 1
`Placebo
`extremities
`not changed
`R
`13
`667010114
`36F
`LCM 400
`musclejerks in hands
`not changed
`R J 2
`
`
`
`754011403
`40F
`LCM 400
`left arm jerkifl
`not changed _I R
`23
`
`
`
`hand jerks/intermittent
`
`
`dizziness & balance
`
`754012407
`51F
`LCM 400
`problems
`not changed
`’i
`24
`755110405
`29M
`LCM 400 j
`dy_s_kinesia, intermittent
`not changed
`R
`94
`
`worsened rapid rhythmic
`‘l—
`movement/intention
`
`
`
`drug interrupted
`
`R
`
`64
`
`tremor
`LCM 600
`26M
`754012605
`Source: AE EP SlDatabase submitted January 2008
`
`
`
`
`
`
`
`
`
`
`
`
`Appendix 11.b. Listing of patients with dyskinesia during open label epilepsy studies (EP 82)
`
`
`
`Rel st
`AE
`ID
`
`AE term
`
`Action
`da
`Outcome
`dose
`
`60700101 1
`
`
`No R
`1785
`
`not changed
`Jerkigjn shoulders and arms
`607001002
`
`No R
`6
`not changed
`Hands jerking
`
`
`
`Bilateral arm /hand jerks
`
`
`
`
`not changed
`66701 1803
`(intermittent)
`R
`'
`459
`
`
`667012410
`Jerking ofhands and arms
`not chan ed
`R
`927
`667018805 789 __'Lerks not changed No R
`
`
`
`
`
`Decreased rapid rhythmic.
`movement R side/ decreased
`
`
`had swing R side./ Abnormal
`coordination, dizziness,
`increased seizure activity,
`
`754011801 not changed tremor.
`
`
`
`
`No R
`754012602
`intermittent limb jerking
`not changed
`
`754015105
`jerkiness
`not changed
`No R
`
`
`Arm and leg jerking (at night)/
`Dose
`
`754016005
`hand tremor, unsteadiness
`reduced
`not changed 755124605 Jerky
`
`
`Source: AE datasets. EP 82. Safety Update Report. January 2008.
`
`
`
`
`
`
`
`
`
`
`183
`
`

`

`Clinical Safety Review
`Lourdes Villalba, MD.
`NDA 22-253, -254, /. Lacosamide for the treatment of partial-onset seizures
`
`'
`
`b(4)
`
`Appendix 12. Standard laboratory assessments and laboratory values considered to be outside
`the normal range in this application.
`
`Eafiamfiarypnrnmeflrunit
`
`Gum-“9mg.”
`
`-
`
`Ziinrkzediy abnormal crimrfin
`
`Efinfiml cilaemfzhw
`
`
`
`
`
`Adooelqissodtseg
`
`£3,13’iz-éLé'LN; Eili‘txULN;
`
`Eiéififlxélfi
`
`23 .. {#:513le; EiEfieULPE;
`
`Margie pmmaame gm}
`
`Iii:ae’bnmfie (mquLii
`
`Bfljxuhém Mal {midi}
`
`Cakfim Ewgifii}
`
`{The 12313303 fing‘fiéi}
`
`Creatfiuéua #:1233313
`
`Gbntmge fimgfljg
`
`Potamfiam {mfiqfii}
`
`Seaman Eufiéqflai
`
`Urge: firid {mgigdg—Z}
`
`meme em93-3
`
`Hem‘mflfi {5‘3}
`
`
`
`5.36.
`
`:2me EG‘L}
`
`I
`
`' 7
`
`ӣ333 3:163
`
`£§m§lhi3¢2§iiéi abedifiqte {@151
`
`184
`
`

`

`Clinical Safety Review
`Lourdes Villalba, MD.
`NBA 22-253, ~254, (‘ Lacosamide for the treatment of partial-onset seizures
`
`”(4}
`
`Appendix 13. Median changes in hematology parameters during the treatment phase in EP 81
`
`Hematology pal
`
`
`
`-020
`
`468
`
`Hematom It ("/a)—
`----
`
`m2
`
`67
`
`
`LCD/I
`LCB'I
`
`
`400mg‘(1 at
`60 Gangr'da}
`
`
`N=471
`\=—203
`
`
`«mo nunn
`
`
`
`RBC countz«UTL
`---
`
`
`
`
`Change End of MP{1
`320
`0 00
`362
`
`
`
`
`Min change Post-Baseline-
`»
`'
`
`
`
`
`Min change Post-Baseline-
`
`35 ‘5
`
`—2 00
`
` Max change Post-Baseline°
`
`
`
`
`Hemoglobin (gfL)
`
`Change End of MP5
`
`Min change Post-Baseline“
`
`
`c
`V
`.
`
`
`Max change Post—Baselme
`
`
` \VBC count (GIL)
`Baseline“
`
`
`
`
`
`
`
`
`
`Neutrophials absoiute (Gl‘L)
`
`—-
`
`-
`
`
`Source: Sponsorstable1n page 467 of ISS.
`
`185
`
`

`

`Clinical Safety Review
`-
`Lourdes Villalba, M.D.
`NDA 22—253, -254, /. Lacosamide for the treatment of partial-onset seizures
`
`[1(4)
`
`Appendix 14.a. Marked hematologic abnormalities in EP S1 and EP SZ
`MM Tom
`LCM Tami
`2. 3132?
`E? yofi £1
`E? Pnafi ’53
`3:944
`
`
`Lanzwspam“:
`
`{mfifmitém
`
`:13‘51312‘3
`
`.
`
` fifmfmxaitflis}
`
`BMMMR {553)
`
`
`53.21,? LL}?
`5,5354 {1 1:
`eases may
`2mm {La}
`
`
`@1315
`hurraza
`213.;- 2313»:
`
`
`WEE tum-fi-Gflc}
`
`
`3.3.51 {253
`251,923 13.13;;
`synergy}
`same-$3
`--
`-
`r a
`
`
`
` Adooelmssoazisan
`
`x ~-
`
`_
`
`.
`
`
`
`firetruphflu’bsnkmfifizl-g
`
`
`
`Platelet count {GEL}
`
`1553:2‘2‘ {$3.3}:
`$2335.? {13:41]
`1.531352? 51%}
`
`Enmogflifls {9%)
`
`
`
`—W 3531295 am
`
`
`
`
`
`
`
`was}: {an
`;
`3353 {9.3.3
`29933 (’32::
`
`
`
`LCM=lacosamide; LLN=lower limit of normal; ULN=upper limit of normal; WBC=white blood cell
`Note: Incidence=n of events/N at risk, where: n of events=number of subjects reporting the abnormality
`afier start of treatment and did not report the reading before start of treatment, and N at risk=number of
`subjects with readings before and after start of treatment who did not report the abnormality before
`treatment. Assessment of marked abnormalities was based on all reported values (including unscheduled visits)
`during treatment.
`
`Appendix 14.b. Marked abnormalities in hematologic parameters SP616
`
`Subjects witn Marked abnormalities for Hematology
`Population: Trial 59636 55
`
`Cohort
`Treatmen:
`E.
`[652315)
`3‘! Lacosamide; anal Placebo
`
`Parameter:
`markedly Abncrmal Value
`
`NBC: <=3.G G/l
`
`Neutrunp‘niia Abs: (LS GI}.
`
`8 (30min)
`Oral Laccsamide/
`
`IV Piacebo
`
`Eosinophils: >=10 §
`
`Site Number / Subject 231220.193:
`
`lDéIlDSZSéét—E
`
`EOE/3.052%?
`
`269i115663§
`
`2133;113:571, 269/13514fi3, 259/‘11524Hfi
`
`Neutzgghils Abs: (3.5
`
`3
`
`008110194#, BEE/11393:}
`
`E7! Lacosamirje/ Oral Placebo
`
`Neutrophiis Abs: «(LS GEE
`
`* only at baseline; # both, baseline and FU. ## Treatment emergent
`
`186
`
`

`

`Clinical Safety Review '
`Lourdes Villalba, MD.
`NDA 22-253, -254
`’Lacosamide for the treatment of partial-onset seizures
`
`11(4)
`
`Appendix 14.c. Marked abnormalities in hematology values in SP757
`
`labia 11.4.1
`
`Subfieets with Markedly Abnezmal Hematoiogy Values
`Popaiazion: Safety Se:
`
`Infusion Duratian
`Parameter:
`{Cohort}
`Markeézy Abnorma: Value
`Site Number f Subject Namha:
`
`
`33—minaee {Cesare Al)
`
`fiemcglobin: {=85% cf L1H
`
`310i§31031*
`
`
`
`
`
`$38: <=3.G G/l
`
`3fl5l330335*, éefi/léeGUI?
`
`Reutroghils Abs: {1.5 G/l
`
`308K3303§5*, SEE/131001;, éflfi/léflSOli
`
`15—minute {Cohort 31)
`
`Hemoglobin; <=85% of LAN
`
`Easinophiis: >=EG %
`
`5001250034€#
`
`400l240013*
`
`fieutroghiis fibs: (1.5 G}:
`
`40D!240816%#
`
`15—minute {Cohort 32)
`
`Eematocrit: C=E$§ of ELK
`
`fiemaglobin: <=85§ of LLN
`
`REC: <=3.0 Gfl
`
`Eosingghiés: >=1§ §
`
`Manecytes: >=2§ é
`
`Platelea Count:
`
`308f130888#
`
`snerzsoeea#
`
`31711317§2*, 490/133021*
`
`600!1600§E%
`
`317!231782*
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Ylel
` ls-minuze {Cohort 52) Reutrophila Abs: (1.5 G11 317x131?§2#, 323/132802*, 409/140021‘,
`
`
`
`lG—minuCE (Cohort C)
`WEE:
`(=349 G/l
`Sflflf150011*
`
`
`
`Reutrfiphiis Abs: <l.5 G/l
`
`500i}500}1*
`
`
`
`
`
`Note: * = Abnormality only at Baseline. # = Abnormality at both Baseline and EOTP.
`## = Abnormality at EOTP but not at Baseline (Treatment-emergent).
`
`APPEARS THIS WAY
`0N ORIGINAL
`
`187
`
`

`

`Clinical Safety Review
`Lourdes Villalba, M.D.
`NDA 22-253, -254V "’ Lacosamide for the treatment of partial—onset seizures
`
`[1(4)
`
`Appendix 15a. Marked abnormalities in chemistries in EP Sl
`LEM
`
`
`Sammy’ény
`LCM Total
`
`
`
`
`
`153:2-133
`35:33:81
`Laboratory parameter
`
`
`
`
`
`{unity‘criiefia
`mm
`
`
`
`
`
`:Eaicimn (111561.)
`
`
`
`132571351313
`
`
`
`35468€Q6J
`
`mus
`
`swamp
`
`H '5."
`HW
`14 :22~33
`4:? — W;
`
`3:357 (L1) mews;
`
`I»)
`
`2293mm
`
`132937132;
`
`Que-use {alaninsfing} {mgi‘dm
`
`£1370
`22%
`Total (hulastzml' {$111091}
`
`4552 {1.2)
`11535:
`
`32153 (1.1:.
`[12”
`
`$546? {1.9} mamas)
`$133955 {11)
`WED?
`
`13%: {1.4}
`{93} (£3.53
`
`1272132 (9;?)
`
`371’??? (1113
`
`
`
`
`
`Adogelqgssodiseg
`
`
`
`
`
`
`
`
`
`
`{1.73
`3;*25?(1.1)
`553525.33
`arsenal} mm (m;
`
`{an
`35635105?)
`224683Ei143
`$939 {9.4)
`
`W?
`am?-
`we
`
`
`ll"
`
`
`
`
`
`23353 {1.3)
`3:252 {113 mews;
`32m (15}
`awards}
`
`
`'0’mWIM
`D5‘}LnQt
`$263
`15468 {9.2)
`92203 I
`1.203% 133.1]
`
`
`
`
`
`
`
`
`
`44338? {£1.43
`3-5.5
`229289 (7.15)
`2159220 (11.8)
`
`
`.
`Brit Mid 91mm.)
`
`
`
`
`Tara! biiirntlin (mgffl)
`
`
`
`Tomi biiirnhia (-giir.) am ALT (5:1;
`
`
`
` Alimiima phasphntme {6:1}
`
`ZSaULN
`was
`9:468
`9:203
`was?
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`23mm
`Albumin (gal)
`<25
`Bea; {many
`
`234.23
`Cmminjne imgidi.)
`
`210
`Bicarbonate {1113110111.}
`
`
`
`531'; {1,31
`
`5.2m (11)
`
`13.5424 (3‘1)
`
`ease (4.2}
`
`2&3565133
`
`was
`
`@3468
`
`mm
`
`0:939
`
`05545
`
`was
`
`was (43.2)
`
`mo;
`
`03355
`
`was (:34)
`
`$2203
`
`3,5933 {9.33
`
`
`
`23439 (5.9}
`
`sums (4.1} Manama}
`
`1-6,?34‘5833
`912595.53
`
`
`
`
`
`GGT=gamma-glutamyltransferase; LCM=lacosamide; LLN=10wer limit of normal; ULN=upper limit of
`normal: Incidence=n of events/N at risk, where: n of events=number of subjects reporting the abnormality
`after start of treatment and did not report the reading beforestart of treatment, and N at risk=number of
`subjects with readings before and after start of treatment who did not report the abnormality before
`treatment.Assessment of marked abnormalities was based on all reported values (including unscheduled
`visits) during the Treatment Phase. Source: Sponsor’s table pg 543 188.
`
`188
`
`

`

`Clinical Safety Review
`Lourdes Villalba, M.D.
`NDA 22-253, -254, .._, Lacosamide for the treatment ofpartial-onset seizures
`
`11(4)
`
`Appendix 15b. Abnormalities in TG levels in EP SI
`
`Inciélcnc: of Treatment Emergent Marked hasmlitiea During the Treatmut Plum:
`- Triglyccrides
`Populatimi Pool 5].
`“MDamnamxd:
`
`
`uoamfiaw
`E flDmgfday
`Elam-d»:
`[N «'71;
`[INT-270]
`{Ii-3 S4]
`Lab Parlmter
`a!!!
`ti)
`mm m
`n/N m
`Timpcint
`——_———— "— '
`Triglycerides:
`[ML-’1]
`-
`[r—l; SxL'lLbl]
`
`fnwlflmgfday
`(ll-253]
`um R}
`
`Ubtal
`ill-1309}!
`um m
`.
`
`Titration
`Maintenance
`Treatment
`
`133/341 (2.91!
`4,3323 [1 . 2;
`111’341 {3.32}
`
`191.253 {3.9}
`43234 fil . PM
`19/25! {3.9)
`
`Iii-455 {3 ll}
`13,3392 {3 .d]
`ZlidEE in} AS}
`
`1!?ng [0.3)
`4’1132 (3.. D3
`4I190 I341}
`
`35!],2714 (2 ‘3]
`2;!‘1071 [:1 .3]
`{£1122};
`[3.7)
`
`A pendix 15c. Marked abnormal chemistries in SP6]
`”£1151: EEJJH ‘3'
`fiubjessa with Ha'kcd Bis/unmask; -e: for Clfinical‘ Chemstzy
`:qulztiun: Eriil 59616 :55
`
`Earamntaz:
`
`Miriaily .anozmal Vain: fiite Rumhgx x’ Sfihject: fi‘mbarm
`
`Cchom:
`Traitmcnc
`PA {60:11:}
`32:3 Lacasmnidef E’é' E'lzcghe
`
`2'1" Lacosamiéref (3:22 Placehz:
`
`GGI‘: 1:3 3: Him”
`
`SGT: >-:E x 01H
`Chclcszeralz >533. waif}:
`
`lDE/EB5‘10#,
`lfiéfififiliéf
`
`lfififlfisiéfii
`
`lfiéa’EBSREé, images 7%
`
`m
`
`
`
`
`
`Adooeiqgssod4339
`
`:3 {30min
`02:: Lacczamide.’ E‘s? Plank:
`
`
`E (39sz
`.:
`I?! Lacosamidcl 9::2 Plzcth-o
`
`Chalesseroi: 295.5 moi}:
`
`895,€lf3176§,
`
`1535116581“, 1181310831§¥
`
`: 7:3 :1 U1}!
`GC-
`Chaiesterai: >E-.5 mulxi
`
`Uri: Raid: >565.66 wolf}.
`
`GET: >=3 M. ml
`35.115 onzte: (15.3 moljl
`falcimz: -<='P.6 ngg‘dl
`
`fihlozide: 22:13.2 malfi
`Giucoze: >=Z§30 :cg/dl
`{haze-ssezal: bfij mglii
`
`
`
`ll‘BEG-ét
`lDE-fli)5§7¥é
`
`106,x’13547#3
`
`106,323.25:
`SOZSJZDLEE‘?
`9031'1510593'
`
`aosnezsu, 265g’i1i553?
`SDEIlGGE‘éf
`3&5!11€§E’*
`
`
`
`APPEARS THIS WAY
`ON ORIGINAL
`
`189
`
`

`

`Clinical Safety Review
`Lourdes Villalba, M.D.
`
`21(4)
`
`NDA 22-253, -254, —" Lacosamide for the treatment ofpartial-onset seizures
`
`
`iaDLE ii.“
`Appendix 15d. Marked chemistry abnormalities in SP757
`Sub3ects with Markedly Abnermal Ezinical Chemistry VERues
`Pnpfliazion: Safety Se:
`
`Infusinn Eurazion
`Parameter:
`{Echort}
`Markeéiy Abnerrfii Value
`Site Number I Subject Number Gfl
`
`IL‘
`A;
`: }=3 3 filfi
`Ln
`DUEES C) CJ UV*2
`SQ-minuze {Cohart A1?
`flh
`
`
`
`SGT: >=3 X §Lfi
`
`Bicazhanate: {E .Q mmfllfl
`
`Chleride: 9:112 mmeijl
`
`Phaspharus: <=2.§ mgidl
`,1
`glucose: <55 mgidl
`
`Chclesterml: >6.5 mmazfl
`GET: >=3 x §Lfi
`
`SGDIZSDUSE§
`
`4’38'.f'14llh3@8#%
`3083230882“, 3101’132001’,
`300f1300931, 3é0i133004§, 408f140853§%
`
`303/130285fi3, 40DE140002*
`
`303i330392§§
`
`3r23130262*, $60Kl¥5804§,
`3F41130201§
`
`€01]140151#,
`
`401f343102%#
`
`Sicarbgnate: (38.0 mmol/i
`
`4Gl/i40112*
`
`Chlsride: >=ll§ mmaifl
`
`401i2401§9*, 481/149111*, 402i140333¥§
`
`Glucose: >=ZGG mgfdi
`
`401f140113%%
`
`Chclesceralz >E.5 mmol/l
`
`302j1302121, éfifif
`f
`SOO?ZSOQG9*, 580
`
`13%, Sflfiiliflflfiflé, SUD/ESOOUéé,
`l
`
`661: >=3 x QLN
`Phaspflorus: <=2.@ mgfdl
`
`301f13013 %, 791/17é108§
`317f231792*
`
`Giucaae: 45% mgjdl
`
`314I131492§§
`
`Chaleszerol: 36.5 mxmlfl
`
`GGI: >=3 x filN
`Chleride: {=90 mmSl/i
`
`Sodium: <12? mmoiil
`
`Cholesterol: >6.5 mmulll
`
`3£3f132334#, 323f1323073, 409!140921#, 401i§40122*,
`402l1402§2¥, 680x16§004§,
`€01fl€03§2#,
`VDl/E7QIUE#,
`7&1/179193fi, 7Qlf1?9104%
`
`301f133182%, 325il32501§
`304/1304fi5‘
`
`304323G435‘
`
`5003150012¥
`
`ls—minuze {Cohsrc 51)
`
`S—minflte {Cahort Bl)
`'
`
`ls—minuze {Cakort 32)
`
`13-minute {Cohort C}
`
`# # Treatment emergent
`
`APPEARS THIS WAY
`0N ORlGlNAL
`
`190
`
`E(
`
`E3
`
`9r
`
`3
`~<
`
`

`

`Clinical Safety Review
`Lourdes Villalba, M.D.
`NDA 22-253, -254, “ Lacosamide for the treatment of partial-onset seizures
`
`M4}
`
`Appendix 16. Measures of central tendency for vital signs in EP Sl.
`
`Eta} aign maammenta firming {Ea :Tfm\MenE Pisaaa in. aubfiaafia WM: pmfial—maei‘aa’imraa
`{EP Baal $15.5
`
`{SKI 411912136er
`E9293
` Parameter fist}:
`
`Time prim-
`
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`191
`
`

`

`Clinical Safety Review
`Lourdes Villalba, M.D.
`NDA 22-253, ~254 -’ Lacosamide for the treatment of partial—onset seizures
`
`M4}
`'
`
`Appendix 17 . Vital Sign changes with LCM intravenous infusion
`
`Table 17.3 Changes'in Systolic BPin study SP616 (single dose)
`
`Parameter {unfit}
`1.6313 5211me
`
`dunafizan granny
`
`APPEARS THlS WAY
`0N 1111311111
`
`
`
`
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`an enema
`
`11111
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`.1
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`-
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`1.11.3111}
`
`19
`
`-0.ii1§151}
`
`4313135)
`
`1519.31)
`
`115111.211
`
`
`
`Parameter (111111}
`LIZ-”zfiinfusfiw
`durafiongmny
`
`gamma
`
`"
`
`1111
`
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`-
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`
`Measured1n the morning. SS= Safetyse
`
`192
`
`

`

`Clinical Safety Review
`Lourdes Villalba, M.D.
`NDA 22-253, -254 "‘ Lacosamide for the treatment of partial-onset seizures
`
`>
`
`,
`h(4)
`
`Appendix 17c. Summary of changes from Baselinel in vital sign parameters by infusion
`duration and time point based on correct infusion duration/dose (SP757 SS)
`Parallax-tar
`$111111}
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`flarafina
`
`111111111}.
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`
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`
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`
`A1103egqgssocg13%
`
`
`
`Parameter
`1mm
`LCM twfnatw
`1511111351111
`
`111111.111
`
`111111.513
`1.1111115;
`
`41151.1
`
`Source: Pg. 668 and 669 ofISS.
`
`193
`
`

`

`Clinical Safety Review
`Lourdes Villalba, M.D.
`
`1
`NDA 22-253, -254, _' Lacosamide for the treatment of partial-onset seizures
`
`”(4)
`
`
`N= 364
`N= 270
`N= 471
`N= 203
`
`Appendix 18. Mean changes in weight by randomization group in EP 81
`Placebo
`’
`LCM 200
`LCM 400
`LCM 600
`n
`‘
`n
`Mean
`n
`Mean
`n
`Mean
`(iSD)
`(iSD)
`(iSQ)
`
`
`
`
`
`
`Mean
`(:tSD)
`
`Body weight
`76.5
`364
`Baseline
`76.8
`339
`Change end Titration
`77.4
`322
`Change end of Maint
`73.2
`33
`Change end oftaper
`Source: Sponsor’s Table 9.5.1 188, original submission.
`
`75.]
`75.1
`74.7
`72.9
`
`78.8
`79.0
`80.1
`74.6
`
`78.5
`80.6
`82.3
`69.8
`
`APPEARS THIS WAY
`0N ORIGINAL
`
`194
`
`

`

`Clinical Safety Review
`Lourdes Villalba, MD.
`NDA 22-253, -254, fi. Lacosamide for the treatment of partial-onset seizures
`
`b
`(4)
`
`Appendix 19. Specific ECG monitoring in the LCM database
`
`8 ECG monitoring in Phase 2/3 studies in epilepsy EP 81
`
`In the double-blind, placebo-controlled trials (SP667, 754 and 755) a standard 12-lead ECG was
`done at each visit (except Visit 2); plasma samples were performed as close as possible to the
`time of the ECG. At Visit 1 (Screening), one 12—lead ECG was done at any time to determine
`trial eligibility. At Visit 3 (Baseline) in SP667, three 12-lead ECGs were performed
`approximately 15 minutes apart prior to dosing; an additional ECG was performed 2-4 hours
`after dosing of trial medication at the approximate time of maximum plasma concentration
`(Cmax). The sponsor ’s OCP summary says Tmax is 0.5-4 hours so some ofthese assessments may
`have missed the Cmax. At all other visits in SP667, one 12—lead ECG was performed 2-4 hours
`after dosing of trial medication. At Visit 3 (Baseline) in SP754 and SP755, three l2-lead ECGs
`were performed approximately 15 minutes apart prior to dosing. At all other visits in SP754 and
`SP755, l ECG was performed at any time after dosing.
`
`During the double-blind phase of these studies, each ECG was transmitted to the central ECG
`facility for manual over-read by a cardiologist. All manual over-reads were done by a single
`cardiologist. The investigator assessed clinical relevance of each abnormal ECG. During the
`trial, if clinically relevant ECG abnormalities were detected, or if a QTc interval 2500ms
`and/or a QTc interval increase of Z60ms from the mean predose QTc value at Baseline was
`detected, a repeat ECG was performed 1 hour later.
`
`ECG monitoring in the epilepsy open-label extension trials
`
`In SP615, SP756, and SP774 ECGs were conducted at all clinic visits and read by central
`readers.
`
`0 ECG monitoring in IV studies
`
`- In the single-dose Phase 1 trials for IV LCM (SP643, SP645, SP658, and SP834 standard 12-
`lead ECGs were taken at regular intervals. There was no central reading.
`
`- In the Phase 2/3 trials of IV LCM (SP616 and SP757), 12-lead ECGs were conducted at
`several time points. In SP616, ECGs were performed during the Screening, Treatment, and End
`of Trial Phase. A single assessment was performed during the Screening Phase within 1 hour
`before the start of the IV placebo infusion. During the Treatment Phase (Days 1 and 2), an ECG
`was performed within 1 hour prior to trial medication in the morning. Several ECGs were
`conducted after the start of infusion of trial medication in the morning and evening. In SP757, an
`ECG was performed after the morning and evening infusion: within 1 hour prior to trial
`medication administration, approximately half-way through infusion, at the end of the infusion,
`and 2 hours after the start of infusion of trial medication. There was ECG central reading.
`
`195
`
`

`

`Clinical Safety Review
`Lourdes Villalba, MD.
`NDA 22-253, -254, "" Lacosamide for the treatment of paitial-onset seizures
`
`3K4)
`
`0 ECG monitoring in healthy volunteers
`
`A Phase 1 thorough QT/QTc interval trial, SP640, was designed specifically to assess the ECG
`Effects of LCM. ECG interval and morphology changes (based on 12—lead ECGs taken at
`specified time points) were analyzed based on ICH Guidance E14. For safety purposes,
`additional l2-lead ECGs were taken as Specified in the protocol. There was central reading.
`
`0 ECG monitoring with the capsule formulation
`
`Standard 12-lead ECGs were conducted on subjects in the supporting Phase 2 trials, SP586,
`SP598, and SP607.
`
`.
`
`APPEARS THIS WAY
`0N ORIGINAL
`
`1'96
`
`

`

`Clinical Safety Review
`Lourdes Villalba, M.D.
`NDA 22-253, -254, / Jacosamide for the treatment of partial-onset seizures
`
`W4}
`
`Appendix 20. Listing Of patients with post baseline QTc (B) Z 450 ms (male) or 2470 ms
`
`(female)
`
`-
`
`
`
`QTc(B) on
`QTc(B)
`QTc (B)
`
`USUBJID
`VISIT
`treatment
`baseline mean
`change
`Female
`
`
`
`
`
`Placebo
`VISIT 4
`471
`436
`35
`755114201
`
`
`LCM 200
`VISIT 12
`474
`439
`35
`
`
`667014501
`LCM 200
`VISIT 6
`475
`440
`35
`
`
`
`
`VISIT 9
`667014501
`LCM 200
`470
`440
`30
`
`
`
`
`
`TRANSITION
`755106201
`LCM 200
`472
`424
`48
`
`
`
`667010206 LCM 400
`VISIT 3
`484
`455
`29
`
`
`
`667010609 LCM 400
`VISIT 6
`471
`443
`28
`
`
`667015705 LCM 600
`VISIT 3
`487
`438
`49
`
`
`Male
`
`
`667012805
`Placebo
`VISIT 6
`453
`420
`33
`
`
`
`VISIT 8
`667017701
`451
`390
`61
`
`
`
`755104305
`Placebo
`VISIT 4
`454
`397
`56
`
`
`
`
`667013204 LCM 200
`VISIT 4
`455
`405
`50
`
`
` VISIT 5 451 413 38
`
`
`667010617 LCM 400
`TRANSITION
`451
`413
`38
`
`TRANSITION
`455
`418
`37
`VISIT 7
`450
`413
`.37
`TRANSITION
`451
`434
`17
`452
`439
`13
`667016924 LCM 400
`
`667016924 LCM 400
`454
`439
`15
`TAPER
`
`'
`667016924 LCM 400
`VISIT 4
`469
`439
`30
`
`667016934 LCM 400
`VISIT 10
`450
`427
`23
`-
`
`667018807 LCM 400
`VISIT 1
`465
`416
`49
`
`754011209 LCM 400
`TRANSITION
`450
`408
`42
`754011807 LCM 400
`VISIT4 .
`451
`405
`46
`
`75401 1904 LCM 400
`VISIT 7
`451
`441
`10
`754012413 LCM 400
`TRANSITION
`451
`436
`15
`
`VISIT 8
`451
`436
`15
`754012413 LCM 400
`754012702 LCM 400
`TRANSITION
`452
`425
`27
`
`754015102 LCM 400
`VISIT 6
`472
`423
`50
`754016006 LCM 400
`VISIT 4
`463
`420
`44
`
`667010601
`LCM 600
`VISIT 7
`457
`431
`26
`
`667010612 LCM 600
`VISIT 7
`451
`429
`22
`
`
`
`
`667015602 LCM 400
`
`197
`
`

`

`Clinical Safety Review
`Lourdes Villalba, MED.
`NDA 22-253, -254_. ’ Lacosamide for the treatment of partial—onset seizures
`
`b(4)
`
`Appendix 21. ECG outlier analyses in studies with LCM intravenous formulation
`
`0 IV Phase 1, single dose studies
`
`The sponsor did not do a PR interval outlier analysis for the Phase 1 IV trials (SP643, SP645, SP65 8, and
`SP834). Overall, there were few subjects who met the QRS duration outlier criteria. The incidence of
`QRS duration outliers was similar for IV and oral administration and also similar between LCM 30—
`minute and 60—minute infusion durations. Only 1 subject had a QRS duration >120ms and none had a
`QRS duration >140ms. Across the Phase 1 IV trials in healthy volunteers, there was no clear evidence for
`QTc prolongation. In total, 85 healthy subjects across the 4 Phase 1 IV trials received IV LCM. Most
`subjects received a single dose of IV LCM 200, except in SP834, in which subjects received a single dose
`of IV LCM 50, 100, 150, or 300, and 4 subjects received IV placebo. In SP643, SP645, and SP658, no
`subject had a QTCB interval ZSOOms following IV LCM. In SP645 and SP658, no subject had an increase
`in QTcB interval Z60ms following iv LCM. In SP834, QTc outlier analysis was not performed.
`
`In SP643, QTc increases from Baseline were always below 60ms and all QTc values were <460ms,
`except for Subject 10020 (randomization number 8001]) who had an increase of QTc from Baseline of
`more than 60ms (68ms) at 4 hours after starting the infusion during Treatment A. Further ECG recordings
`showed changes from Baseline of less than 60ms. The subject was withdrawn from the trial according to
`the withdrawal criterion of an increase of QTc from Baseline by more than 60ms as defined in the trial
`protocol. This case has been discussed under section 7.3: “Other AE of interest” of this review.
`
`0 Outliers in IV in Phase 2/3 IV LCM trials in subjects with partial-onset seizures
`
`- Study SP616. The frequency of outliers in EP SP616 is presented in the following table.
`
`Table 616a.lncidence of PR outliers during treatment phase in SP616.
`
`Cohort A {613mm
`
`Cohen: 3 {33min}
`
`>2 501315
`
`.
`
`'
`1
`‘
`
`Parameter
`
`Criteria
`Overall
`>200m3
`>220me
`>330m5
`
`Treatment—emerge nE/Bas 61.11121
`“>2 IS) 01115
`>2 3 was
`192501215
`
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`>2 00135
`$28135
`
`Oral Lam:seuz'rzlele;t
`IV Placebo
`———-——
`
`IV Laccsvamidef
`Ora: Piacebo
`
`Oral Laessamide!
`IV Placebo
`——
`
`IV Lacs-samicief
`{Jral Placebo
`
`R
`
`(%J
`
`n; N
`
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`
`mi R
`
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`
`n! N
`
`[%§
`
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`
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`
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`
`‘
`
`.‘
`.
`
`3! E
`0f 1
`D;
`E
`
`198
`
`

`

`Clinical Safety Review
`Lourdes Villalba, M.D.
`NDA 22-253, -254, / Lacosamide for the treatment of partial-onset seizures
`
`.
`
`b‘d)
`
`Overall: subjects meeting the specified criteria at any timepoint during the Treatment Phase without regard to
`Baselinel or Baseline2. n = Number of subjects meeting the specified criteria out of the set of subjects at risk (N). N
`= Number of subjects in the Safety Set for Overall and the number of subjects who did not meet the criteria
`at the specified Baseline for treatment—emergent summaries. Treatment—emergent is defined as meeting the criteria
`for any ECG during the Treatment Phase and not meeting the same criteria at the specified Baseline. Source:
`Sponsor’s Appendix EP.11.3.2.
`
`Overall, 15 to 27% of subjects met the PR interval outlier criteria. The frequency of outliers did
`not markedly differ between the oral and IV treatment groups, although there is a trend to more
`outliers in the oral LCM groups.
`'
`
`QRS interval outliers with >100 ms duration are presented in the following table.
`
`Table 616b.. Incidence of TE QRS duration outliers with respect to baseline 1 at any time in SP616
`
`Cohort A {66min}
`
`{cs-hart. 8 {38min)
`
`Oral Lacosamide}
`IV Laccsamide/
`Ural Lacesamidex
`IV Placebo
`Oral Fiaceho
`IV Fiacehc
`—~———— ——————— ——
`:, H
`{%}
`
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`Oral Piacabo
`
`(%fi
`
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`
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`
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`
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`
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`Czicaria
`Svezeli
`>260m3
`kififlms
`>240m5
`
`zeazment—amergenajsaseiinei
`>1Q0m3
`hififlms
`>240m5
`
`Treatmeet—emergentffiase:inez
`>1Q0ms
`fiEZGma
`
`Overall is the number of subjects meeting the specified criteria at any timepoint during the Treatment Phase without
`regard to Baselinel or Baseline2. n = Number of subj ects meeting the specified criteria out of the set of subjects at
`risk (N). N = Number of subjects in the Safety Set for Overall and the number of subjects who did not meet the
`criteria at the specified Baseline for treatment-emergent summaries. Treatment-emergent is defined as meeting the
`criteria for any ECG during the Treatment Phase and not meeting the same criteria at the specified Baseline. Source:
`Appendix EP 11.3.8.
`'
`
`Overall, 14 to 25% fulfill the QRS duration outlier criteria. The incidence of QRS duration
`outliers was similar for IV and oral administration and also similar between LCM 30-minute and
`
`60-minute infusion durations. No subject had a QTc interval 2500ms. In addition, no subject had
`a change from Baseline 1 (predose in SP616) Z60ms.
`
`In SP616, a total of60 subjects were treated with IVLCM with 10 to 20 patients
`per treatment group. 15-30 % ofpatients had outlier results in PR and QRS
`intervals in both treatment groups. No definitive conclusions can be made about
`the comparative safety of the 30 and 60 ms IV infusion and or the oral versus IV
`formulation.
`
`199
`
`

`

`Clinical Safety Review
`Lourdes Villalba, M.D.
`NDA 22-253, -254, ,. Lacosamide for the treatment ofpartial—onset seizures
`
`0(4)
`
`- SP757
`
`Across all infusion duration groups and dose categories in SP757 the frequency of PR interval
`outliers appear to occur more often in the 30-minute infusion as compared to the other durations
`(15 and 10 minutes). Two subjects in the 15—minute infusion group had a treatment—emergent PR
`interval >250ms while on LCM 200mg/day. The number is too small to draw any conclusions
`regarding comparative safety of these infusion rates. The incidence of PR interval outliers with
`respect to Baselinel (Baseline1=ECG prior to first IV LCM administration) anytime during the
`Treatment Phase by dose category is presented in the following table.
`Table. 757a. PR interval outliers in SP757
`
`Incidence of treatment-emergent PR interval outliers with respect
`tn Basei'mel anytime during the Treatment Phase by time tategary
`(LCM 309mgfiay—aififimgfday, LCM SEBmgfiuy—fififimgféa};
`LCM 100mgfiagrwsfifimgfihy3-(Sl’fi7 SS)
`LCM infusion duration
`
`33059 categm‘y 2‘ PR criteria
`
`2.031 Efifi-flfimgféay
`'
`
`at}; {5%}
`
`RW- (”#133
`
`iseg
`
` Adooeiqgssod
`
`LCM Sfifl-éflemgiday
`
`mm M m}
`
`was M M
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`7
`0?
`
`Wkfilamssmide; mmitizaemd; Sfiafety Set
`Note: amber aimiijezts fleeing the Specified Maia em {if the set ofmhjects at risk 3% REES member of
`Enigma win did not meat the attain: Seminal.
`Data source: 5.3.5.2.? HP: 8375? Eebéa 125.2
`
`As seen in this table, approximately 24% of patients in the 30 minute infusion group, 15% in the
`15 minutes infusion group and 4% of the 10-minute infiision group, fulfill the >200 PR outlier
`criterion as compared to baseline 1. A higher percentage of patients also had QRS >100 ms in
`the 15 and 10-min infusion as compared to the 30 min infusion.
`
`200
`
`

`

`Clinical Safety Review
`'
`Lourdes Villalba, M.D.
`NDA 22-253, —254, / cacosamide for the treatment of partial-onset seizures
`
`b
`
`(4)
`
`Table 757b. Treatment emergent QRS outliers in SP757.
`
`LCM infusion duration
`15—minute
`
`Ifi-zm'nute
`
`33"}?
`
`:-a :7
`
`{'22}
`
`mt§=mcommiég Wilkezmd; 3:3:‘Safat3' Set
`Note: nwmhr-afmbjeus meeting the specified criteria we: a: ”she set afsubjects at risk (N: 29:33:; amba' m’
`mitten; who did no: mes: file (maria at Baselinel ..
`
`Source: Sponsor’s table in page 168 of Cardiac Report.
`
`There were no subjects who had a QTcF interval ZSOOms during the trial. There were no subjects
`who had a change from Baseline2 260ms (Baseline2=Baseline ECG from subject’s original trial)
`in QTcF interval during the trial. One subject had a change from Baselinel Z60ms
`(Baseline1=ECG prior to first iv LCM administration) in both QTcF and QTcB intervals; this
`subject did not discontinue from the trial. Also in SP757, 1 subject had a QTcB interval ZSOOms
`post-Baseline during the trial; this subject was discontinued from the trial because of this
`increase in QTcB. There were 2 subjects who had a change from Baselinel Z60ms in QTcB
`interval during the trial and there were 4 subjects who had a change from BaselineZ Z60ms in
`QTcB interval during the trial. These subjects (change from Baselinel or BaselineZ Z60ms) were
`not discontinued from the trial.
`
`APPEARS THlS WAY
`0N ORlGlNAl
`
`201
`
`

`

`
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