`
`
`
`
`
`
`
`
`
`
`Table 3: Patient Disposition
`LCM
`
`
`';
`430 Am:
`i’lareimz
`Parameter
`n %}—_—
`
`M“
`
`
`
`sagas?)
`
`arose;
`
`54 {261)
`
`$4693)
`
`22.3 (39.13
`
`rare)
`
`3:59)
`
`1711239}
`
`23' {19.9)
`
`
`
`
`
`
`21 {15.5}
`
`U)
`we
`a {3.6}
`.6)
`41:
`2. {3.3)
`
`
`we
`
`r (1.7)
`
`2 (as;
`
`.2 (or)
`
`m (6.5)
`
`LCM 2 iammide; Maxi fl moeifloxafia
`Reproduceé from page 64 of sponsor’s study report
`
`Randomized Set (RS): Ail ranéomized subjects were incioded in the RS.
`
`Safety Set (SS) Alt randomized suhjects who received at least '2 dose of triai medicatioo
`were hrciuded in the SS.
`
`Phatmacodynamic Set (PBS): Ali 88 subjects who completed through Day 3 in the
`moxifloxacio group and through Day 6 in the lacosamide ané piaceho groups and had a
`sufficient B—iz data to caiculate. reliabie estimates for the phammcodynamic parameters
`were incinded in the PDS. Any subject with a major protocol deviation that wouid render
`the ECG data. um‘etiable or render the data incomparabie among subject groups was
`excluded from the PBS. The set of subjects that comprised the PDS was defined prior to
`unblinding. Subjects were replaced if they did not complete through Day 3 for subjects
`assigneri to moxifioxacih or through Day 6 for subjects assigned to either placebo or
`lacosamide», including completion of the H— 12 assessment on Day 3/6. Subj ects who were
`repiaced were excluded from the PBS and, therefore, were excluded from the primary
`anatysis.
`
`All randomized subjects received at ieast 1 dose oftrial medication and therefore were
`inciuded in the SS. 'IWenty-seven subjects discontinued from the triai prior to completing
`the dosing regimen and thus were not included in the PBS, An additional 6 subjects were
`missing 1-1-12 ECG data at greater than 3 time points on primary ECG recording days;
`these subjects were classified as mater protocol deviators and were excluded from the
`PDS.
`
`Table 4 provides a smemary of baseline demographics for the study patients by
`randomized group.
`'
`
`NDA ~_
`Lacosamide Film-Coated Tablets
`
`h(4)
`
`, 50, 100, 150, 200, 250, 300 mg
`Original NDA Reviewa
`
`251
`
`

`

`Table 4-: Baseline Demegrapifics
`LCEK
`
`Piaeebu
`@452
`
`409mgfday
`83:69
`
`'k’faxi
`33:54
`
`All Sufiiects
`3324'?
`
`Parameter
`
`Age Gears)
`
`MeanéSD)
`
`24.3, (6.1)
`
`24.7" {5.4)
`
`24.9 {5.3)
`
`23.1 {7.3)
`
`24.? (6.6}
`
`Min. my;
`Sex
`
`£845
`
`£844
`
`18—43
`
`,
`
`18—44
`
`£845
`
`Male (3336])
`
`30- (48.4)
`
`27 {45.8)
`
`23 {39.4}
`
`2‘? {39.9)
`
`112 {45.3}
`
`Female {za[%})
`Race
`
`3‘2 $31.6)
`
`33 {35.8)
`
`43 {60.6)
`
`2? {50.0)
`
`135 ($4.18
`
`White (113%)
`
`51 (32.3}
`
`34 {98.0)
`
`6:5 {915}
`
`48 {88.9)
`
`218 (88.3}
`
`Black {11%)}
`
`Asian {99%)}
`
`2 (3.23
`
`3 (3.23
`
`Silver {219%}
`
`7 (31.3)
`
`2 (£71)
`
`3 (5.0)
`
`2 (3.3)
`
`3 {4.2}
`
`l {1.4}
`
`2 {2.8}
`
`3 {5.6)
`
`2 {33)
`
`l {1.9)
`
`9 {3.63
`
`8 (3.2}
`
`12 (4,9)
`
`
`
`i?‘l.é (9.6)
`158-191
`
`170.3 {8.6}
`150-291
`
`179.0 {3.5)
`ESE-188
`
`”2.0 (SH)
`13—293
`
`170.9 (8.8)
`1504,93
`
`'Weight (kg)
`
`Mean {SD}
`
`12.94;
`(£1-39)
`
`?2.9{}
`(£2.69)
`
`69.36
`(11.85)
`
`758i
`{13.34)
`
`72.53
`(12.33)
`
`MiszK
`
`504-1094
`
`411104.45
`
`4?.2—962
`
`' 53-64894
`
`47.240931
`
`124.738.0415
`
`25.05 {3.13)
`
`23.91 {3.95}
`
`25.32 {3.22)
`
`24.74 (3.15)
`
`18.9—32.0
`- 19-0320
`£89311}
`19.7-31.4
`19.0-32.9 V
`.
`BMI : bcdy mass mm; LCM = lamamiée; Max = maximum; Min mmisfitmma; Maxi B moxifioxaeie; SD —“=
`5?de deviating SS = Safety Set
`Reproduced from}; 67 out of 8001 of sponsor’s study report
`
`4.2.7.2 Statistical Analyses
`
`4.2. 15'. 2.1 Primmy Analysis
`
`The primary analysis was based 0:} a non-ilfierim‘ity comparison of each LACOSAMXDE
`group with placebo using 1-sided 95% confidence intervals (or, equivalently, the upper
`limits of 2-sided 96% cenfidence intewals) for maximum time-matched change fiom
`Baseline in QTcI (calculated by taking the maximum of all time-annulled changes for
`each subjefi for each day).
`
`Confidence intermls were produced using an analysis of covariance (ANCQVA) model
`with effects for treatment and gender, and time-matched baseline QTcI as a covariate.
`Additionally. 2-sided confidence intewals for mximum time-matched change from
`baseline in QTcI were presented Within each treatment greup.
`
`Lacosamide Film-Coated Tablets
`50, 100, 150, 200, 250, 300 mg
`Original NDA Review
`
`“(4)
`
`

`

`£701" ECG parameters, the basetine values were obtained from the H-IZ assessment on
`Day -I. For time-matched changes, the baseline at. each time point was the median of the
`3 values obtained at each time point. The primary variable for this triai was the maximum
`timeimateheé change in QTcI from Baseline to Day 3 for the momfloxacin group and
`Day 6 for the placebo and lacosamide groups. All analyses of the primaty valiabte were
`based on data from the 1—1-12 recorder. The primacy anaiysis was based on a non-
`infeziority comparison of each lacosamide, group with placebo using I-sideé 95%
`confidence intervals (or, equivalently, the upper limits of 2-sided 90% confidence
`intewals). Confidence intervals were produced using an MCOVA mode? with effects for
`treatment attd gender2 and time-matched baseline QTcZ as a covariate‘ The statistical
`model was fit. with all 4 treatment. groups; therefore, the estimate of the variance was a
`pooled estimate obtained from all it treatment groups. Time-matched baseiine QTcI was
`the Baseline value from the time point on Day -t., which corresponds to the time point on
`Day 6 or Day 3 at which the maxitmim change occurs.
`
`The sponsor also did a time averaged analysis. For time-averaged changes, the baseline
`value was obtained as follows: 1) the median of the 3 values at. each time point on Day -1
`was obtained, and 2} these 12. values were averaged to obtain the time—averaged baseline
`value.
`
`The difi‘erence in the maximum time-matched change fi'om Baseline in QTcI between the
`400 mgfday tacosamide group and ptacebo was -4.3 and between the 800 mayday
`lacosamide group and placebo was -6.3. In both cases, the upper limit of the 2-sided 90%
`CI (-0.5 and ~25 for 400 mgfday iacosamide and 800 mgfday tacosanaide, respectively)
`was below the 10 ms non-inferiority margin, thereby demonstrating that there is no
`relevant increase of QTcI caused by lacosamide. The sponsor claimed that assay
`sensitivity was demonstrated since the mean difference between moxifloxacin and
`placebo was 10.4 ms and the lower 95% confidence bound was >8, thereby showing a
`statistically significant effect over placebo. Results were similar for the SS and for mates
`and females.
`‘
`
`The statistical analysis of the maximum time-matched change on Day 6 (Day 3 for
`moxifioxacin) in QTct is presented in the following table. The sponsor reported the 2-
`sided 90% confidence interval, as wet! as the 95% interval.
`
`Table 5: Maximum”? time—matched change on Day 6 (Day 3 for moxifloxacin) (PBS)
`Endpoint
`Treatment Difference
`LShiean Comparison
`(SE)
`
`90% C?4;
`
`95% CT1
`
`Treatment
`
` A0101)elmssod4399
`
`
`
`4.3 (2.2
`
`—6.3 (23)
`10.4 (2.3
`Note: A = placebo, B = LCM dOGmngay= C = LCM 800mg/dny= D = moxifloxncin
`Note: p-values and confidence intervals are based on an ANCOVA model with effects for treatment and gender and
`time-matched Baseline 011:! as a covariate.
`.
`Note: Maximum time-antched change fi'om Baseiine to Day 3 for moxifloxacin group.
`ANC‘OVA = analysis ofcovmimice; Ci = confidence interval ofmean; LSMeans = least squares mean; LCM =
`lacoanmide; Evlmii "moniflomcin; PDS m phmmacodynnmic. set; SE " standard enter
`3. Confidence intermls are for the treatment differences
`
`*Mean of maximum over time Within each individual subject
`
`--
`3/
`Lacosamide Film-Coated Tablets '
`50, 100, 150, 200, 250, 300 mg
`Original NDA Review
`
`Mai
`
`253
`
`

`

`w
`(D
`a
`
`1 m 2
`
`. %
`
`Table 6 and Table. 7 U’ve the results by hour on day 3 and day 6, respectively.
`
`Table 6: Non—Inferiofl'ty Analysis of Time—Matched Change in QT‘cI (ms) by Day
`and Time — ANCOVA Modei- Pharmacodynamic Set
`2.3 Mam
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`.3 = w; fia‘fimgfézy'. C W 2.2!!! Efiamfdw. E ‘1 fiaxiflwxufir.
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`Table 7: Non-Inferiority Analysis of Time—Matched Changes in QTci (ms) by Day
`and Time — ANCOVA Mode} - Pharmacodynamic Set
`
`2.5 Mean:
`"images: 2.15-2:encem
`§G§ Cunfideace intervals
`Timefiaim
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`. Son-inieziczisy :mariaw: are. Tunas! on We 35:57:: $imi§u a5 917% C3: So: 32;: diffezrmm lamp-.4: m away: and
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`and Sigmuamm Eauiint mum: n a zanh’nwu: c‘a’uinatg.
`
`The 31mm made}. was £3.15 amatafivif at each as:
`paint.
`
`time: 631:,- 2:g 3 and my 6 w: aulyacé. Emlyn: So-
`:3; is 2.: bsseé an a.“ firm {3:3 3 far auxifiuncin.
`
`4.2. 7. 2.2 Categorical Anabs‘sis
`A sulmnmy ofthe number of absoiule and change from Baseline outliers in QTcI by day
`and time is presented in the following table.
`
`NDA "'""
`Lacosamide Film-Coated Tablets
`50', 100, 150, 200, 250, 300 mg
`Original NDA Review
`
`”(4}
`
`254
`
`

`

`Table 8: Summary of subjects with a new onset QTCI outlier value during the
`Treatment Phase {Phgrmamdymamic Set)
`
`480mgidey
`
`Nee‘fi
` Panemeter
`
`
`
`
`QTCI
`$58311: to ”380%
`8 {1.5.4}
`
`
`
`
`$86113 ro- willing
`.0
`
`
`eiéflm
`0
`
`QTd
`
`
`humane £30 to mm
`
` Emerge of-zaofin‘e
`
`mm: hresanfikfi; Maxi: maxifloxadn; PBS z nhmodniamit 5e:
`Reproduced from page 78 of sponsor’s study report
`
`0
`
`A
`
`in (19.2}
`8
`
`23 {$3.83
`it
`-
`
`
`
`There were no ECGS with a QTCI of 480 ms or greater at any post-Baseiine time point
`that were not present. at Baseline. The percentage of subjects with new onset values for
`QTcI of): 450335 was 7, 5, 2, anti 15 in the piacebo, 400 mgfday iacosannde, 800 mgi’day
`lacosamide, and moxifloxacin goups, respectiveiy. One subject in the placebo group and
`4 subjects in the moxifioxacin group had changes fi‘oni baseline of 2 601113 in QTeI. No
`subject in either lacoeamide gong) had a change from baseline in QTeI that was 60 ms or
`greater at any time point during the trial. The percentage of subjects with increases in
`QTCI that were 30 to 60 ms was higher in the nioxifloxecin group and placebo groomg
`54% and 37%, respectively, compared with 2'?% and 19% in the 400 trig/day and 800
`mg/day lacosamide groups, respectively. The con'esponéing percentages with QTCI
`increases between 30 and 60 ms in the ali randomized set were 56, 3’2, 25, 19, for
`Moxifioxacin, placebo, 400 mg/day lacosamide and 800 mg/day lacosamicte,
`respectively,
`
`4.2.7.3 Safety Analysis
`
`1 subject had an SAB. a spontaneous abortion 9 éays following her last
`No subject died.
`dose of 800 mg of iacosann'de.
`1 subject had a 2 minute episode of syncope about, 12
`hours afier being administered 800 mg of lacosamide on day 4; the sponsor reports no
`ECG being available at the time of occurrence.
`
`2? subjects failed to complete the study (see Table 3); 15 of these were in the lacosarniée
`800 mg treatment group, 3 in the lacosamiée 400 mg treatment group, 7 in the placebo
`group, and none in the moxifioxacni group. The reasons are as follows:
`
`0
`
`o
`
`G
`
`2 subjects (both in the 800 mg lacosamide treatment group and both female) were
`withrhnwn due to ABS; i for neck pain and the other for heinatemesis due to
`'Mallory—Weiss tear.
`
`8 additional female subjects in the 800 mg qd lacosamide treennent gmup and l
`fenmle in the 400 mg qd group withérew consent while experiencing ABS. All of
`these were related to some combination of dizziness, nausea and vomiting. The.
`sponsor does not report any abnormaiities or ECG for any of these subjects.
`
`3 subjects in the 800 mg qd lacosamide treatment. group and 4 subjects in the
`piacebo group withdrew consent without ongoing ABS
`
`‘
`NDA ‘1
`Lacosamide Film-Coated Tablets
`50, 100, 150, 200, 250, 300 mg
`Original NDA Review
`
`.
`
`“4)
`
`255
`
`

`

`o
`
`4 subjects in the 800 mg qd laeosamide treatment group, 1 in {he 400 mg qd
`group, and 3 subjects in the piacebo group wiflidrew for “other”
`
`ABS were experienced more freqeemly by subjects in the 880 mg/day iacosamide
`treatment group and consisteé primaiiiy of events in the nervous system. 2274 of the 312
`ABS were assessed by the investigator as mild and the rest as moderate. The most
`common events in the 8-00mg/day1aco-samide gmup were dizziness (54.9% of subjecie),
`113113ea€26.8%)fi headache (225%), hygaoesthesia era} (21. %)5 and feeling dmfik (15.5%),
`
`Review-91’? comment: iMany ofthe .S'ubjeci wiflzdrawai’s appear to be due to poor
`folerabiiizfy qfthe 800 722g dose aflzzcommide. How-3:91:87: I5 suly'ects (~ 7% offize rota!)
`wifizdr’ewfiar unclear reason. For a pkarmacokinez‘ic study theai’thy .mbjecte, this
`number is quite. high and may qfl'ecr the reliabiliiy ofz‘he data.
`
`4.2.7.4 Clinical i’hmmacology
`
`4.2-. 7.4.1 Pharmacokinefic Analysis
`
`The mean laeosamide plasma concentration-time profiles after multiple era}
`administratious of 400 ring/day and 800 mgiday over 6 days are shown in Figure 1.
`
`Figure 1: Mean Piasma Conceiitrafien—Time Prefiles of Lacosamide by Treatment
`
`on day 6
`
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`
`mm?!“-
`
`«0—H 1m mummy;
`
`H—B—B LCM enema/day
`
`The main metaboiit‘e for lacosamide is SPMIZSOQ. The mean SPMIZSOQ piasma
`concentration-time profiles after muffiple oral administmtiens of 200 mg bid and 400 mg.
`bid over 6 Gays are shown in Figure 2
`
`NDA “=4
`Lacosamide Film-Coated Tablets
`50, 100, 150, 200, 250, 300 mg
`Original NDA Review
`
`b(4)
`
`256
`
`

`

`Figure 2: Mean Plasma Concentration—Time. Profiles of the Main Metabolite for
`Laeosamide (SPfMiZSOQ) by Treatment on day 6
`
`10-3
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`Figure '2: Mean Piasma Concentration—Time Profiles of the Main Metabolite for
`
`Laeosamitle (SPMiZSOQ) by Treatment on day 6
`
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`
`The mean maze-matched change from baseline in QTcI and mean plasma concentration of
`lacosamide after multiple oral dosing of 400 mgfciay (top) and 800 111giۤay (boftom) are
`shown in Pigure 3.
`
`NDA —/
`Lacosamide Film-Coated Tablets
`
`50, 100, 150, 200, 250, 300 mg
`Original NDA Review
`
`h(4)
`
`257
`
`

`

`figure 3: Mean Time—Matched Change from Baseline in QTcI and Mean Plasma
`Cenoentratien—Tfime Profiies for Lacosamide by Treatment 0;: day 6 3,; i.
`11x3
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`I» AAHean Time-Matched Change in are] ims)
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`
`fwcaimm
`
`Reproduced from Sponsor’s Figure 51 on page 892 and 893 in study report SP640
`
`4.2. :7. 4.2 Exposure-Resp anse A naiysis
`
`A simple linear model was (leveioped to evaiuate the reiationship between {hue-matched
`change from baseline QTcI and piasma concentration of Iacosamide. The results are
`illustrated in Figure 4. The linear con‘eiatioa between time-matched change from baseline
`QTcI was very weak.
`
`d__
`
`NDA
`Lacosamide Film-Coated Tablets
`50, 100, 150, 200, 250, 300 mg
`Original NDA Review
`
`33(4)
`
`258
`
`

`

`Figure 4': Time—Matched Change from Baseline in. QTCI as. Piasma Concentration
`of Lacosamide
`
`
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`
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`QTCIJITE -
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`
`Reproduced from Sponsof-s Figure 6.1 011 page 906 in study report $13640
`
`APPEARS mas WAY
`0»: ORIGINAL
`
`NDA -”
`Lacosamide Film-Coated Tablets
`50, 100, 150, 200, 250, 300 mg
`Original NDA Review
`
`“(4)
`
`I
`
`259
`
`

`

`According to the sponsor, there appeared to be a small increase in the ?R interval with
`increasing concentration of lacosamide (see Figure 5)
`
`Figure 5: Time—Matched Change from Baseline in PR vs. Plasma Concentratibn of
`Lacosamide
`
`mm»
`
`Reproduced fi'om Sponsor’s Figure 6.5 on page 910 in study report SP640
`
`5
`
`REVIE‘WERS’ ASSESSD'IENT
`
`5.1
`
`STATISTICAL ASSESSMENTS
`
`The sponsor desigmtecl the QTcI as the pl‘llllfil'y QT assessment. QTcI = QT/ (RR?
`Where the coefficient £3 was derived, separately for each subject, by regression of 10g QT
`on log RR using only the bageline ECG data.
`
`There were no time points at which the l-side(195% upper bound for the difference
`between either of the lacosamide treatment groups and the placebo group exceeded 10 ms
`in terms of the change in QTcI. The same results were aiso confirmed using QTcB, and
`Qch. Assay sensitivity was demonstrated with Moxifloxacin since at multipie time
`points, the lower bound of 90% CI is above 5 ms; however, no multiple endpoints were
`ad'justed though for the assay sensitiviw analysis.
`
`Figure 6 shows the baseline corrected difference in changes in QTcI between
`moxifloxacin and placebo over time on day 3 as estimated by the ANCOVA model at
`each timepoint.
`
`APPEARS THES WAY
`
`0N ORIGINAL
`
`NDA -——-'
`Lacosamide Film-Coated Tablets
`50, 100, 150, 200, 250, 300 mg
`Original NDA Review
`
`h(4)
`
`260
`
`

`

`Figure 6: LS Means and 2—sided 96% Bounds for Moxifloxacin AAQTcIs on Day 3
`(Ali Randomized Set)
`
`DeliaBciia
`
`Tab}: 9 provides the LS mean changes in QT’CI for each day and each timepoint based on
`the ANCOVA modei in the ali ramlomizeci data set.
`
`Table 9: Changes from baseline in Q'fcI in the Ali Randomized Set (FDA)
`
`QTCI‘
`
`
`
`
`
`LSMEAN Afrom 90% '
`Afmm 90‘}:
`LSME
`Afiom
`N LSMFAA
`LSIZSE)
`(SE)
`Piacebo
`LB
`Placebo
`(SE)
`Placebo
`(SE)
`III
`IIIIII
`IIInI E
`IIII III
`III I E
`-I
`
`
`
`I II
`
`II
`
`NDA "
`Lacosamide Film-Coated Tablets
`50, 100, 150, 200, 250, 300 mg
`Original NDA Review
`
`h(4)
`
`261
`
`

`

` fiacebo
`
`Lacosamide 480 mg
`A £1an096
`Placebo
`UB
`
`(SE)
`
`
`
`Lacosamide 800 mg
`LSEIEAN A 15an
`{SE}
`.63
`
`Mnm'floxacin
`USMEAN
`(SE)
`65
`
`98%
`
`Piaceho
`
`aI-
`32
`79
`{19) “In
`(26
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`NDA ’ ‘3
`Lacosamide Film—Coated Tablets
`50, 100, 150, 200, 250, 300 mg
`Original NDA Review
`
`b(4)
`
`262
`
`

`

`For the categoricat analysis the sponsor reportect that in the PDS set the percentage of
`subjects with new onset. values for QTCI of 2 4501115 was ’7, 5, 2. and 35 in the placebo.
`4001:2gfdaylacosannde, .800 Ingiday lacosamide, and moxifloxacin groups, respectively.
`In the all randomized set this reviewer founci that there were 3 additional subjects with
`QTcI 3 450 ms in the lacosamide 803 group. In this set the percentages were 6, 5, 6, and
`1? in the ptacebo, 400 tug/day lacosamide, 800 tug/day tacosamide, and moxifloxacin
`groups, respectively.
`
`In the PDS set. the percentage of subjects with increases in QTcI that were 30 to 60 ms
`was higher in the moxifloxacin group and ptacebo groups. 54% amt 37%, respectively,
`compared with 27% and '19%in the 400mglday and 800mgéay lecosamide groups,
`respectively. in the all randomized set the percentages with QTct increases between 30
`and 60 ms were 32, 25, 19, and 56, it}. the placebo, 408 angictay lacosamide M,- 800
`mg/éay iacosamide, and moxifloxacin groups, respectively.
`
`5.2
`
`CLINICAL i’HAREVIACOLOGY ASSESSMENTS
`
`Reviewer is comments: The schedsfedplasma cancentmfions Inconvenient: on Day 5
`(morning and evening pie-dose} were notprmzidedfor the anafivszls. Furthermore, there
`were 11 female tepiacementsfor dropouts in the szwmfkerapeufic fi‘eafl’iteflt group and
`310 male reptacements.
`
`5.2.1 QTIB Corrections
`
`The obsewed QT-RR interval relationship is presented in Figure ‘7 together with the
`Bazett’s (QTc-B)‘ Fridericia {QTcF}, and individuai correction (QTCB methods. ‘
`
`Both the QTCF and QTcI are reasonable QT correction methods removing the heart rate
`effect illustrated by a horizontal trend in the QT vs. RR relationship. Thus, the QTcI
`correction method was used for the concentration QTc atmlysis to be compambte with the
`sponsor’s analysis.
`
`NDA ———
`Lacosamide Film-Coated Tablets
`50, 100, 150, 200, 250, 300 mg
`Original NDA Review
`
`M4)
`
`‘
`
`263
`
`

`

`Figure 7: Baseline (lay QT, QTcB, QTCF, and QTcI vs, RR (Each Subject’s Data
`Points are Connectefi with a Line).
`
`
`
`RR interval {133882}
`
`5.2.2. AAQ’E‘CE and Concentration Time Profiles
`
`The AAQTCI (baseiine and pianebo corrected QTCE) versus lacosamide and the main
`metabolite SPMEZSOQ concenfratian is plotted in 8. The largest AAQTCI of
`approximateiy -8 msec change was obsewed at the iime to file peak of Iacosamide and
`SPM12809 conceata‘ation {tum}.
`
`APPEARS T3453 WAY
`0N ORIGENAL
`
`,
`NDA ’— 7
`Lacosamide Film—Coated Tablets
`
`b‘4)
`
`50, 100, 150,200, 250, 300 mg
`Original NDA Review
`
`264
`
`

`

`Figure 8: Mean 'AAQE‘CI, Lacosamide, and SPME2809 concentrations vs. Time for
`
`therapeutic dose of 408 nag/day (blue line) and supra—therapeutic. {Iose of 800 mgiday
`(red line).
`
`
`
`MeanProfiles
`
`~8
`
`20
`
`$0$5
`
`2.4
`
`1.8
`
`12
`
`16
`
`20
`
`24
`
` 0
`
`4
`
`8
`
`12
`
`Time (hours)
`
`5.2.3 Exposure—Response. Modefing
`
`The relationship between AAQTCI and concentratiom of laeosamide and the main
`_ metabolite SPM1’2809 wee havestigated by 9.9ng a linear mixed-effects model. Data
`collected from the two dose groups (400 mgfday am! 800 mg!day) were pooled for the
`anaiysis.
`
`Both Iacosamide and the main metabolite SPM12809 were found to shorten the QR:
`intervai. Table 10 and Table 11 summarize the results of the iacosamide and SPM12809
`
`concentration-QTCI analyses. No statistieai significant intercept was identified and mode;
`2 was applied for both the lacosamide and the metaboiite analysis.
`
`NDA /
`Lacosamide Film-Coated Tablets
`50, 100, 150, 200, 250, 300 mg
`Original NDA Review
`
`“(4)
`9,
`,
`
`265
`
`

`

`Table 16: Exposure—Response Analysis of Lacosamide associated AAQTCI
`
`i’l'ololggtion
`
`
`
`
`Estimate (90% CI);
`
`-Value
`.
`
`
`
`Model 1: AAQTCI = Interce t + slogaflogfl f:n'essmaide cone}
`
`4.17 (-1.55, 9.89}
`Intercept, ms
`
`
`0.23
`
`
`
`Slope, ms per lag/11114
`‘2'93 63:? ‘05?)
`
`
`
`
`Residual Variability, ms
`14.2
`
`fixed Interee 1t
`Medel 2: AAQTCI = Interce t + slogefloggLacesamide com:
`
`
`Intercept, ms 0
`
`
`
`
`..
`.
`-I.33 (-1.88, -0.78)
`Slope, ms pet pg mm
`0.000:
`
`
`Reskiual Variability, msec 14.2
`
`
`Made] 3: AAQTQI = slope*iog(Lacosamiée cone) (No Intercept)
`
`-1,26{-1.82, -0,70)
`Slope, ms per pg lmL
`0.0003
`
`
`Residual Variability, 1115;
`14.3
`
`
`
`
`
`Table 11: Exposure—Respanse Analysis of SPMIZSGQ assaciated AAQTCI
`
`Prolongation
`
`Estimate (90% CI);
`
`ap-Value
`
`
`Model 1: AAQTCE = Interce- t + slogefloggSPM 12809 cone)
`
`
`-1.21 (-2.78, 0.35)
`Bitercept, ms
`
`0.20
`-4.27 {-6.56, -1.98)
`
`
`Slope, ms per gig/ml,
`
`0.003
`
`
`14.2
`
`
`Residual Vafiability, msec
`
`
`
`Model 2: AAQTCI = Interce t + slogfilogflSi’M 12809 cone) Fixed Interce r t
`O
`
`
`Intercept, ms
`
`
`
`i
`_
`-5.08 (-7.11, -3.05)
`
`Slope. ms pel gig/ml:
`43.0001
`Residual V’afiabfiim msec“
`
`
`
`Model 3: AAQTCI = slope*log(SPM 12809 cone) (N0 Intercept)
`
`-5.64 (-7.70, -3.58)
`
`
`
`Slope, ms per gzgt’m};
`
`<0.0001
`'
`
`
`
`Residual Variability, ms
`v
`150
`
`Based on model 2 for both lacosamide and SPM12809, the predicted AAQTCI interval at
`the meanpeak lacosamide and SPMlZSO9 concentrations after steady-state dosing of the
`
`NDA \
`Lacosamide Film-Coated Tablets
`, 50, 100, 150, 200, 250, 300 mg
`Original NDA Review
`
`“(4)
`-
`
`266
`
`

`

`proposed therapeutic {400 mg/day) and sumo-therapeutic (800 mg/day} doses ale
`presented11] Tame 12 and Tabie 13.
`
`Tame 12: Predicted Change of AAQTCI Interval at Steady State Peak Lacosamide
`Concentration
`
`
`
`
`
`9 .
`a
`Predicted chance in A235 3121 interval (ms)_
`,
`
`Mean
`90% Confidence hltewal
`086 Gmup
`
`
`
`400 mg/day (steady—state)
`
`(-4.52, -I.88)
`I
`-3.26
`‘
`.
`Mean Cmx (I 1.1 Ilgfmi)
`
`
`300 mgfday (steady-state)
`
`
` Mean Cmax (21.7 ng/mi)
`
`(-5.78, 45.40)
`
`
`
`
`
`480 mglday (steady—state)
`
`
`800 mgx‘day (steady-state)
`
`
`4.71
`
`(-2.39, 4.03)
`
`Tame 1'3: Predicted Change of AAQTCI Interval at Steady State Peak SPM12809
`Concentration
`
`
`
`Predicted chance in AAQ’FCI mtezval (ms)
`Dose (310111)
`Mean
`90% Coefidence {menial
`
`
`Mean Cmax (1.40 ngimi)
`
`Mean Cm (2.61 zzgz’ml)
`
`.
`
`
`
`I
`
`4.88
`
`(-6.83, -2.93)
`
`The relationship between lacosamide and 8PM 12809 concentrations and AAQTcI are
`visualized in Figure 9. The raw AAQTcI vs. lacosamide and SPMIZSOQ‘ concentration are
`shown in Figme 9 top left and right graphs. The goodness-of—fit is iilustmted in the
`middle iefi and right graph of Figure 9 showing the observed mid-quartile concentrations
`and associated mean AAQTci (90% CI) reasonably wéthin the mean (90% CI) predicted
`AAQTCI (black line with shaded giey area). The mean (90% CI) p1eciieted AAQTCI at
`mean Cm aftex steady-state dosing of the:apeutic dose (400 mgjday) and supra-
`thempeutic dose (800 szday) are shown111 the bottom iefi and fight graphs of Figure 9.
`
`APPEARS THIS WM
`
`0?! ORHGINAL
`
`.
`NDA —
`Lacosamide Film-Coated Tablets
`
`[1(4)
`
`50, 100, 150, 200, 250, 300 mg
`Original NDA Review
`
`267
`
`

`

`Figure 9. (Top) AAQTCI. vs. Iacosamide (Left) and SPMIZSQQ (Right) piasma
`coucentratiom (Middle) Mean (90% Ci) predicted AAQTCI vs. lacosamide piasma
`concentration {Mack 13:36 with shaded grey area} with the observed miquuartiie
`concentrations and asseciated mean (90%CI) AAQTCI overlaid for therapeutic (Dine)
`and supra—therapeutic (red) doses. (Boflom‘) Predicted AAQTCI at mean me after
`steady-state dosing. of therapeutic dose (408 mgx‘clay, blue line) and supra-therapeutic
`dose (806 mgfday, red fine)
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`
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`
`NDA —’
`Lacosamide Film-Coated Tablets
`
`“(4)
`
`50, 100, 150, 200, 250, 300 mg
`Original NDA Review
`
`268
`
`

`

`5.3
`
`CLINICAL ASSESSMENTS
`
`None of the adverse events identified as significant in the ICE E314 guidelines (Le,
`sudden death, torsade de pointes, venfrimtar mchycaz‘diag syncope, anci seizures) were
`observed during the trial.
`
`6
`
`APPENDIX
`
`6.1
`
`TABLE 01" STUDY ASSESSMENTS
`
`
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`
`ND,A ——'-
`Lacosamide Film-Coated Tablets
`
`M4)
`
`50, 100, 150, 200, 250, 300 mg
`Original NDA Review
`
`269
`
`

`

`Inn-gum“:uuuuuuu.n-n-xn-m-nnun--u-u-x-n-u-x-------n gggggggu-uuuuuuuuuu-III-nxnnug-nsuu.u-u-u-nu-n.......:-
`
`This is a representation of an eiectronic re 0rd that was signed electronicaliy and
`this page is the manifestation of the electronic signature.
`
`/ 8/
`
`Stephen Grant
`7/25/2007 12:00:36 PM
`MEDICAL OFFICER
`
`Christifle Garnett
`7/25/2007 12:26:47 PM
`PHARMACOLOGZST
`
`Christofier Tornoe was the clinical pharamcology reviewer.
`
`Joanne Zhang
`7/25/2007 01:22:08 PM
`BIOMETRICS
`
`Tristan Massie
`7/25/2007 01:27:12 PM
`BIOMETRICS
`
`Norman stockbridge
`7/25/2007 02:56:42 PM
`MEDICAL OFFICER
`
`A
`
`ND,A
`Lacosamide Film—Coated Tablets
`50,100,150,200,250,3001ng
`Original NDA Review
`
`b‘4)
`
`270
`
`

`

`4.4 OCP Filing and Review Form
`
`
`Office of Clinical Pharmacology
`New Dru A I :lication Filin and Review Form
`General Information About the Submission
`
`__—
`
`
`,
`,
`22-253, 22-2540W‘”
`Brand Name
`No proposed trade name
`
`
`
`
`
`'
`
`-
`
`NDA Numbers
`
`Suresh Doddapeneni
`
`0&0
`
`“(All
`
`09/28/2007
`05/26/2008
`
`Sponsor
`
`Schwarz Biosciences, Inc
`
`Oral /IV
`
`(DAARP)
`. DCPZ
`OCP Division(1,2,3,4, 5)
`Drug Class —
`DAARP
`Medical Divisions
`
`
`
`OCP Reviewer
`Emmanuel O Fadiran
`Indication(s)_
`Diabetic Peripheral
`Neuropathic (DPN)
`
`
`Partial onset seizures
`
`
`
`
`Film-coated tablets —
` OCP Team Leader
`
`Dosage Forms/Strength
`
`
`50, 100, 150, 200,
`
`
`
`250, 300 mg
`
`
`
`
`'
`In ection — 10 mg/ ml
`
`Uosing Regimen
`
`
`oute of Administration
`
`
`
`
`
`
`Date of Submission
`Estimated Due Date of OCP
`Review
`PDUFA Due Date
`Priority Classification
`7/28/2008
`Division Due Date
`Submission Type
`5/26/2008
`
`
`Clin. Pharm. and Biopharm. Information
`“X” if
`Number of
`Number of
`Critical Comments If any
`included at
`studies
`studies
`filing
`submitted
`reviewed
`_
`
`
`
`STUDYTYPE
`Table of Contents present and
`sufficient to locate reports, tables,
`data, etc.
`Tabular Listing of All Human Studies
`
`
`
`
`
`Reference Bioanalytical and
`
`Healthy Volunteers—
`
`2
`multiple dose:
`
`"
`NDA .——-—-
`Lacosamide Film-Coated Tablets
`50, 100, 150, 200, 250, 300 mg
`Original NDA Review
`
`M4)
`
`
`
`l l 2
`
`__—
`
`__—
`
`3 2
`
`— 3 —
`x —
`,
`_ 2 _
`x —
`271
`
`
`
`
`
`
`
`
`
`
`

`

`
`Request for deferral for
`studies in pediatric patients
`
`
`
`below -- year