CENTER FOR DRUG EVALUATION AND
`
`RESEARCH
`
`APPLICA TI0N NUMBER:
`NDA 22—253 & 22—254
`
`STATISTICAL REVIEW! SQ
`
`

`

`Office of Biostatistics
`
`US. Department of Health and Human Services
`Food and Drug Administration
`Center for Drug Evaluation and Research
`Office of Pharmacoepidemiology and Statistical Science
`
`STATISTICAL REVIEW AND EVALUATION
`
`CLINICAL STUDIES
`
`NDA/Serial Number:
`
`22,253
`
`Drug Name:
`
`Lacosamide
`
`Indication(s):
`
`Adjunctive Therapy for Partial Seizures
`
`Applicant:
`
`Schwarz
`
`Submission Date:
`
`Sept, 28 2007
`
`Review Priority:
`
`Standard
`
`Biometrics Division:
`
`. Division of Biometrics I
`
`Statistical Reviewer:
`
`Tristan Massie, Ph.D.
`
`Concurring Reviewers: Kun Jin, Ph.D., Team Leader
`
`Kooros Mahjoob, Ph.D., Deputy Division Director
`
`Medical Division:
`
`Neurology
`
`Clinical Team:
`
`Norman Hershkowitz, M.D., Ph.D., Acting Team Leader
`
`Russell Katz, M.D., Division Director
`
`Project Manager:
`
`Jacqueline Ware
`
`Keywords:
`
`log transformation, analysis of covariance, drop-outs, dose-response, multiple
`comparisons
`
`

`

`Table of Contents
`
`LIST OFTABLES.......................................... 4
`
`LIST OF FIGURES .............................................................................................................................................'........ 4
`
`1
`
`EXECUTIVE SUMMARY .................................................................................................................................5
`
`1 .1
`1.2
`1.3
`
`CONCLUSIONS AND RECOMMENDATIONS ....................................................................................................... 5
`
`....5
`BRIEF OVERVIEW OF CLINICAL STUDIES .................................................................................................
`STATISTICAL ISSUES AND FINDINGS .............................................._.................................................................6
`
`2
`
`INTRODUCTION ............................................................................................................................................... 7
`
`2.]
`2.2
`
`OVERVIEW......................................................................................................................................................7
`DATA SOURCES ..............................................................................................................................................8
`
`3
`
`STATISTICAL EVALUATION ........................................................................................................................8
`
`EVALUATION OF EFFICACY ..............................................................................................................
`...8
`3 .1
`
`Study 667 ............................................................................................................. 8
`3.1.1
`
`Objectives .............. 8
`3.1.1.1
`Study design ................................. 8
`3.1.1.2
`
`Statistical Analysis Plan.
`............................................................ 10
`3.1.1.3
`Patient Disposition .............................................................. 13
`3.1.1.4
`
`..... 16
`Baseline Demographics.
`3.1.1.5
`
`Sponsor's Results ...............
`17
`3.1.1.6
`
`
`Reviewer’s Results ............................................... 22
`3.1.1.7
`
`Secondary Analyses ....................................................................... 26
`3.1.1.8
`Study 754 ......................................................
`..26
`3.1.2
`
`Study Design and Statistical Analysis Plan..
`.26
`3.1.2.1
`
`Patient Disposition .....................................................................................................
`.29
`3.1.2.2
`
`Baseline Demographics and Disease Characteristics .....................................................
`30
`3.1.2.3
`
`Sponsor’s Results .......................................................
`31
`3.1.2.4
`
`
`Reviewer’s Results.....
`32
`3.1.2.5
`
`Secondary Analyses
`................................................................................................
`35
`3.1.2.6
`.............................................. 36
`Study 755
`3.1.3
`
`Objectives ...............
`. 36
`3.1.3.1
`Study Design ..................
`36
`3.1.3.2
`Statistical Analysis Plan.
`37
`.................................
`3.1.3.3
`
`Patient Disposition .............................................................
`42
`3.1.3.4
`
`Baseline Demographics.....................
`43
`3.1.3.5
`
`Sponsor's Results ............
`45
`3.1.3.6
`
`Reviewer’s Results ........................................... 48
`3.1.3.7
`
`Secondary Analyses ......................................................................................... 50
`3.1.3.8
`EVALUATION OF SAFETY .............................................................................................................................. 51
`
`3.2
`
`4
`
`FINDINGS IN SPECIAL/SUBGROUP POPULATIONS .............................................................................51
`
`4.1
`4.1.]
`4.1.2
`4.1.3
`4.2
`4.2.1
`4.2.1.1
`4.2.1.2
`4.2.1.3
`
`GENDER, RACE AND AGE .............................................................................................................................51
`Gender ................................................................................................................................................. 51
`Race ..................................................................................................................................................... 53
`Age ...........................................................................
`
`OTHER SPECIAL/SUBGROUP POPULATIONS .................................................................................................. 54
`Individual Sites and Countries....................................................
`...54
`
`Study 667 .......................................
`54
`
`Study 754 ...................................................
`55
`
`
`Study 755 .................................................................................................................... 56
`
`5
`
`SUMMARY AND CONCLUSIONS ................................................................................................................ 57
`
`

`

`5.1
`5.2
`
`STATISTICAL ISSUES AND COLLECTIVE EVIDENCE .......................................................................................57
`CONCLUSIONS AND RECOMMENDATIONS ..................................................................................................... 58
`
`

`

`, LIST OF TABLES
`
`Table 1 Study 667: Schedule of Trial Procedures ........................................................................................................ 1 0
`Table 2 Study 667 Patient Disposition ......................................................-.......................................................... 1 5
`
`Table 3 Study 667 Baseline Demographic and Disease Characteristics ............................................................ 16
`Table 4 Study 667: Median Seizure frequency from Baseline to Maintenance Phase (FAS) ...................................... 17
`Table 5 Study 667: Statistical Analysis for Percent Reduction of Seizure Frequency over Placebo at Maintenance
`Endpoint Population: Full Analysis Set ............................_........................................................................................... 17
`Table 6 Study 667: Statistical Analysis for 250% Responder at Maintenance Endpoint ........................................ 18
`Table 7 Study 667: Response to Treatment from Baseline to Maintenance By Gender (Full Analysis Set) ............... 19
`Table 8 Study 667: Responders to Treatment from Baseline to Maintenance By Region (Full Analysis Set) ............20
`Table 9 Study 667: Reviewer’s Results for Primary Analysis of Seizure Frequency over Maintenance Period .........22
`Table 10 Study 667: Assessment of the Impact of Dropouts on Primary Analysis .....................................................25
`Table 11 Study 754: Patient Disposition (Safety Set) .................................................................................................29
`Table 12 Study 754 Baseline Demographics and Disease Characteristics ..................................................................30
`Table 13 Study 754: Median seizure frequency per 28 days by treatment (Full Analysis Set) ................................31
`Table 14 Study 754: Statistical analysis for percent reduction of seizure frequency over placebo for the Maintenance
`Phase (Full Analysis Set) .............................................................................................................................................32
`Table 15 Study 754: Statistical analysis of 250% reduction in seizure frequency for Maintenance Phase (FAS) .....32
`Table 16 Study 754: Primary Analysis Result .............................................................................................................33
`Table 17 Study 754: Sensitivity Analyses for the Assessment ofthe Impact of Missing Data/Dropouts ................... 35
`Table 18 Study 755: Schedule of Trial Procedures - All subjects ...............................................................................39
`
`Table 19 Study 755 Disposition (Full Analysis Set) ............................................................................................43
`Table 20 Study 755: Baseline Demographics and Disease‘Characteristics .................................................................44
`Table 2lStudy‘755: Median seizure frequency per 28 days by treatment Population: FAS ........................................46
`Table 22 Study 755: Statistical analysis for percent reduction of seizure frequency over placebo for the Maintenance
`Phase Population: Full Analysis Set ............................................................................................................................46
`Table 23 Study 755: Statistical analysis of 50% responder rates for the Maintenance Phase .....................................47
`Table 24 Study 755: Primary Analysis Result of Double Blind Seizure Frequency During Maintenance (FAS) .......48
`Table 25 Study 755: Sensitivity Analyses for the Assessment of Missing Data/Dropout Impact ...............................50
`Table 26 Treatment Effect by Gender in Pooled FAS Population (inc. 667,754,755) ................................................ 53
`Table 27 Pooled Analysis of Double Blind Seizure Rate ............................................................................................ 58
`
`LIST OF FIGURES
`Figure 1 Study 667: Median Percent Reduction of Seizure Frequency from Baseline to Maintenance Endpoint
`Population: Full Analysis Set ...................................................................................................................................... 18
`
`Figure 2 Study 667: Variation of Treatment Group LSMeans by Region .............................................................21
`Figure 3 Study 755: Median percent reduction of seizure frequency from Baseline to Maintenance Phase Population:
`Full Analysis Set..........................................................................................................................................................47
`Figure 4 Study 667: Assessment of Consistency of Treatment Effects by Gender ....................................................52
`Figure 5 Study 667: Treatment Effects by Site (Excluding 200 mg group) ..................................................
`...55
`Figure 6 Study 754: Treament Effects by Site...........'..................................................................................................56
`Figure 7 Study 755: Treament Effects by Site ............................................................................................................. 57
`
`

`

`1 EXECUTIVE SUMMARY
`
`1.1 Conclusions and Recommendations
`The data from the three phase 3 trials seem to support the efficacy of Lacosamide as adjunctive
`therapy for partial seizures. The 400 mg/day dose was represented in each study and was
`statistically significantly better than placebo in each study. The 600 mg/day dose was also
`significantly better than placebo in the two studies it was included in, but there was no
`compelling evidence that the 600 mg/day dose provided added improvement over the 400
`mg/day dose. The 200 mg/day dose was significantly better than placebo in one ofthe two
`studies in which it was included. Although in both studies in which it was included it’s effect
`was numerically smaller than that of the 400 mg/day dose, in one, the difference was very small
`and, in both studies, the exploratory comparison ofthe difference between it and the 400 mg/day
`dose was not nominally significant.
`
`1.2 Brief Overview of Clinical Studies
`
`The primary trials included in this application, SP667 (US and Europe), SP754 (US only), and
`SP755 (non-US only), were designed to be adequate and well-controlled trials to evaluate the
`efficacy and safety ofLCM 200mg/day (SP667 and SP755 only), 400mg/day, and 600mg/day
`(SP667 and SP754 only) versus placebo in subjects with uncontrolled partial-onset seizures
`taking 1, 2, or 3 (SP754 and SP755 only) antiepileptic drugs (AEDs) with or without vagal nerve
`stimulation (VNS). These 3 trials were similar in design; all were multicenter, randomized,
`double-blind, placebo-controlled trials to assess the efficacy and safety of 200 (SP667 and SP755
`only), 400 (SP667, SP754, and SP755), and 600mg/day (SP667 and SP754 only) of LCMas
`adjunctive therapy in adult subjects with partial-onset seizures. In SP667, subjects were
`randomized in a 1:1:1:1 ratio to placebo, LCM 200mg/day, LCM 400mg/day, or LCM
`600mg/day; in SP755, subjects were randomized in a 1:121 ratio to placebo, LCM 200mg/day, or
`LCM 400mg/day; and in SP754, subjects were randomized in a 122:1 ratio to placebo, LCM
`400mg/day, or LCM 600mg/day.
`The design of these studies represents a standard placebo-controlled, parallel group, adjunctive
`therapy trial in this indication similar to that used in the development of other newer AEDs. An
`8-week Baseline Phase was considered necessary to adequately assess Baseline seizure
`frequency due to spontaneous fluctuations of seizure frequency in this patient population. A
`Baseline seizure frequency of at least 4 partial seizures per 28 days was deemed sufficiently high
`to detect both decreases and increases in seizure frequency during the Treatment Phase.
`Furthermore, the duration of the Maintenance Phase (12 weeks) was chosen to be consistent with
`the European Agency for the Evaluation of Medicinal Products (EMEA) “Note for the guidance
`on clinical investigation of medicinal products in the treatment of epileptic disorders” (EMEA,
`2000).
`
`

`

`1.3
`
`Statistical Issues and Findings
`
`Each ofthe three phase 3 studies had a protocol amendment to change the sample size. In the
`case of study 667 the reason for the change was that during the trial it was determined, based on
`tracking of patient completion status (blinded), that there were fewer dropouts than originally
`expected. Because of this the sponsor decided to reduce the number to be enrolled from 500 to
`486 and the number to be randomized from 450 to 432. This change was made on 03 October
`2003 after the first patient was enrolled (on 11 Feb 2002) and before the last subject completed
`(on 07 May 2004). For studies 754 and 755 the reason was that the original sample size
`calculations had been based on data from a different drug, Levetiracetam, since there was limited
`data on Lacosamide available at the time. Once study 667 was completed the sponsor wanted to
`update the sample size calculations for studies 754 and 755 using the Lacosamide data from
`study 667. For study 754 the sample size was increased from 60 to 100 subjects in the placebo
`group, 120 to 200 subjects in the 400mg/day group, and 60 to 100 subjects in the 600mg/day
`group. For study 755 the sample size was increased from 100 subjects per treatment group to 154
`subjects per treatment group. The changes were made on 27 Jan 2005 for both study 754 and
`study 755, both of which were underway but not yet completed (754: 16 Aug 2006 and 755: 24
`Jan 2006). However, the sponsor confirmed on April 11, 2008 that there was no unblinding of
`the internal trial data behind any of these sample size changes. Therefore, the sample size
`changes are not considered a serious issue.
`
`The 600 mg/day Lacosamide group, the highest dose of Lacosamide studied for epilepsy and
`included in two of the three phase 3 trials, had a substantial number of dropouts: 42%, in study
`667, as compared to 26% for the 400 mg/day group 21% for 200 mg/day and 11% for placebo
`and 33%, in study 754, as compared to 21% for the 400 mg/day group and 14% for the placebo
`group. The primary analysis of the double blind seizure rates was statistically significantly
`reduced for the 600 mg/day group as compared to the placebo group (p=0.0257 in study 667 and
`0.0089 in study 754). The primary analysis was based on seizure data from the maintenance
`period only, if the patient had provided seizure data during the maintenance period and, where
`possible, when there was no data from the maintenance period, it was based on data from the
`titration period. The results for the 600 mg/day vs. placebo comparison were slightly sensitive to
`handling of dropouts as evidenced by the loss of significance when a patient’s missing data after
`dropout was imputed with the patient’s baseline seizure rate (p=0.1055 in study 667 and 0.0588
`in study 754). This may be due to the high dropout rate for the 600 mg/day group. However,
`several other approaches to missing data imputation including imputing with the seizure rate
`during titration instead of during baseline did not lead to a loss of significance. The 400 mg/day
`group which had slightly less of a problem with dropouts was more robust to imputations for
`missing data after dropout.
`
`Based on the primary intent-to-treat analysis of patients that had post-baseline seizure data there
`was very little evidence that the 600 mg/day dose provided any additional benefit beyond the 400
`mg/day dose in either ofthe two studies in which it was studied. In addition the dropout rate was
`higher for the 600 mg/day group. Median percent changes from baseline in seizure rate were
`39.0 for 400 mg/day and 39.6 for 600 mg/day in study 667, and, in study 754, they were 37.3 for
`400 mg/day and 37.8 for 600 mg/day. In study 667 the primary analysis, of the logarithm
`
`

`

`transformed double blind seizure rate, actually suggested that the 400 mg/day group'had a
`numerically greater improvement than the 600 mg/day group.
`
`2
`
`INTRODUCTION
`
`2.1 Overview
`
`Lacosamide (LCM; SPM 927; previously referred to as harkoseride, [R]-2-acetamido-N—benzyl-
`3-methoxypropionamide, ADD 23403 7) is a member of a series of functionalized amino acids
`that were specifically synthesized as anticonvulsive drug candidates. Lacosamide is being
`developed for the treatment of adults with partial-onset seizures and adults with diabetic
`neuropathic pain. The associated IND is 57939.
`
`The primary efficacy evaluation for the use of LCM for adjunctive therapy in adults with partial-
`onset seizures is based on 3 trials: SP667 (conducted in the United States [US] and Europe),
`SP754 (conducted in the US), and SP755 (conducted in Europe and Australia).
`
`These 3 trials were similar in design; all were multicenter, randomized, double—blind,
`placebo-controlled trials to assess the efficacy and safety of LCM 200 (SP667 and SP755 only),
`400, and 600mg/day (SP667 and SP754 only) as adjunctive therapy in adult subjects with
`partial-onset seizures. In SP667, subjects were randomized in a 1:1:1:1 ratio to placebo,
`LCM 200mg/day, LCM 400mg/day, or LCM 600mg/day, and in SP755, subjects were
`randomized in a 1:121 ratio to placebo, LCM 200mg/day, or LCM 400mg/day. However, in
`SP754, subjects were randomized in a 1:231 ratio to placebo, LCM 400mg/day, or
`LCM 600mg/day.
`
`Subjects were male or female, age 18 to 65 years in SP667 and 16 to 70 years in SP754 and
`SP755. Included subjects had uncontrolled epilepsy with simple partial-onset seizures and/or
`complex partial-onset seizures with or without secondary generalization.
`In addition, subjects were on a stable dosage regimen of 1 to 2 (SP667) or 1 to 3 (SP754 and
`SP755) concomitant AEDs with or without additional concurrent VNS. The dosage of
`concomitant AEDs was kept constant for 24 weeks prior to entry into the Baseline Phase and
`throughout the trial.
`
`In each trial, subjects were enrolled and entered into an 8-week Baseline Phase. Only subjects
`who reported 24 partial-onset seizures per 28 days on the average, with seizure-free period no
`longer than 21 days during the Baseline Phase, were to be randomized. After randomization, the
`subjects began double-blind treatment as follows: a 4- (SP755) or 6-week (SP667 and SP754)
`forced titration up to the respective randomized dose of LCM (200, 400, or 600mg/day) or
`placebo (a 1-step back-titration of LCM 100mg/day or placebo was allowed in the case of
`intolerable adverse events [AEs] at the end of the Titration Phase), a 12-week Maintenance
`Phase on the achieved randomized (or back-titrated) dose, and either a 2—week Transition Phase
`or a 2- (SP755) or 3-week (SP667 and SP754) Taper Phase.
`
`

`

`In order to facilitate trial blinding, subjects randomized to LCM 200 and 400mg/day in SP667
`received placebo for the first 4 and 2 weeks of the double blind phase, respectively, and,
`similarly, subjects randomized to LCM 200mg/day in SP755 received placebo for the first 2
`weeks.
`
`2.2 Data Sources
`The data for studies 667, 754, and 755 are located in the following directories, respectively.
`
`\\cdsesub1\EVSPROD\NDA022253\0000\m5\datasets\ep-sp667\analyses
`\\cdsesub1\EVSPROD\NDA02225 3\0000\m5\datasets\ep—sp754\analyses
`\ \cdsesubl \EVSPROD\NDA022253\ 0 OOO \m5\datasets \ep-sp755 \analyses
`
`The study reports for studies 667, 754, and 755 are located in the following directories,
`respectively.
`
`\\cdsesub1\EVSPROD\NDA022253\0000\m5\53-clin-stud-rep\535-rep-_effic-safe§gtud\epilepsy\5351-stud-r_ep_-
`contr\ep—sp667
`
`\\cdsesub1\EVSPRCD\NDAO22253\0000\m5\53—clin-stud-rep\535-rep-effic—safet_v-stud\epilepsy\535 l-stud-rep-
`contr\ep-sp754
`
`\\cdsesub1\EVSPROD\NDA022253\0000\m5\53-clin-stud-rep\535-rep-effic-safefl-stud\epilepsy\535 l-stud-rep-
`contr\ep-sp755
`
`3 STATISTICAL EVALUATION
`
`3.1 Evaluation of Efficacy
`
`3.1.1 Study 667
`The first patient was enrolled on 11 Feb 2002 and the last subject completed on 07 May 2004.
`
`3.1.1.1 Objectives
`The primary objective of this trial was to evaluate the efficacy of SPM 927 (Lacosamide)
`administered concomitantly with 1 or 2 AEDs in subjects with or without additional vagal nerve
`stimulation (VNS) who currently have uncontrolled partial seizures with or without secondary
`generalization. The secondary objectives were to evaluate the safety of SPM 927 and the dose
`response relationship of SPM 927 with regards to efficacy and safety and to examine steady-state
`plasma concentrations of SPM 927 and concomitant AEDs during oral administration.
`
`3.1.1.2 Study design
`This trial was a multicenter, double-blind, placebo—controlled, 4-arm, trial of oral SPM 927 as
`adjunctive therapy in subjects with partial seizures with or without secondary generalization.
`The subjects were enrolled and entered into an 8-week pretreatment phase to obtain baseline data
`8
`
`

`

`(Baseline Phase). After randomization the subjects were treated for up to 21 weeks in a double
`blind fashion: 6 weeks forced titration up to the respective randomized dose of SPM 927
`(200mg/day, 400mg/day, or 600mg/day) or placebo (one step in back-titration of lOOmg/day or
`placebo was allowed at the end of the Titration Phase), a 12-week Maintenance Phase on the
`achieved randomized dose, and either a 2-week Transition Phase or a 3-week Taper Phase. The
`2-week Transition Phase was required for subjects who completed the Maintenance Phase and
`chose to enroll in an open—label extension trial of SPM 927 (study SP615), the primary objective
`of which is to collect long-term safety data for SPM 927. The 3-week Taper Phase was required
`for subjects who chose not to enroll in the open-label extension trial of SPM 927 or who did not
`complete the Maintenance Phase. The randomization ratio was 1 : l
`: l : 1 (Placebo : 200
`mg/day : 400 mg/day : 600 mg/day)._Randomization was stratified by country, and allocated to
`sites within each country.
`
`Trial medication was to be administered in two equal oral doses per day at 12-hour intervals (4 .
`tablets in the morning and 4 tablets in the evening). Subjects randomized to 600 mg/day were to
`titrate up by 100 mg/day per week for 6 weeks to 600 mg/day. Subjects randomized to 400
`mg/day were to receive placebo during week 1 and week 2 and were to titrate up by 100 mg/day
`per week during week 3 through week 6 to 400 mg/day. Subjects randomized to 200 mg/day
`were to receive placebo during week 1 through week 4 and were to titrate up by 100 mg/day per
`week during week 5 and week 6 to 200 mg/day.
`
`Diagnosis of partial seizures was to be based on the International Classification of Epileptic
`Seizures of the International League Against Epilepsy.
`
`Each subject (or caregiver) kept a diary to note the daily seizure activity and seizure type from
`the beginning of the Baseline Period until the last visit. The following information was to be
`recorded in each subject’s diary:
`
`- Seizure type
`
`' Seizure frequency
`
`- Any AE’s, including physical injury that occurred and any concomitant treatment that was
`
`used, if applicable.
`The efficacy parameters were to be measured based on:
`
`° Seizure records
`
`APPEARS THlS WAY
`
`0N ORIGINAL
`
`

`

`Table 1 shows the schedule of trial procedures.
`
`Table 1 Study 667. Schedule of Trial Procedures
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`3.1.1.3 Statistical Analysis Plan
`
`The Date of the first draft of the SAP was 14 Nov 2003. The final draft date was 11 Mar 2004
`and the date of the final SAP was 17Jun 2004.
`
`The assessment of efficacy is based on seizure frequency. There are two important efficacy
`variables. For the FDA, reduction in seizure frequency (variable 1) was to be the primary
`efficacy variable and the responder rate (variable 2) was to be the secondary efficacy variable.
`For Europe the responder rate (variable 2) was to be the primary efficacy variable and the
`reduction1n seizure frequency (variable 1) was to be the secondary efficacy variable.
`For FDA:
`
`1) Reduction in seizure frequency per 4 weeks from baseline to maintenance phase.
`
`10
`
`

`

`Seizure frequency per 4 weeks was to be calculated for the Baseline and post-Baseline
`Maintenance Phases as follows. For seizure frequency per 4 weeks, the number of days used to
`standardize the seizure frequency (SF) was to be based on the number of days (D) for which seizure
`information was provided: SF = (Number of Seizures) x (28 / D)
`The inferential statistical analysis, based on an ANCOVA model with terms for treatment and
`region, was to be performed on log-transformed seizure frequency using the transformation of
`ln(x+l), where x is equal to the seizure frequency. Log-transformed average seizure frequency
`during the Baseline Phase was to be used as the covariate. The seizure frequency between
`treatment and placebo was to be compared using least squares (LS) means. The percent reduction
`over placebo was to be estimated as (l - the exponentiated difference of LS means between
`treatment and placebo) multiplied by 100.
`If a seizure cluster was reported, it was to be assigned to the correct seizure type. The highest
`recorded daily number of seizures ofthat seizure type during that phase for the corresponding
`subject was to be used as the imputed number of seizures for the day on which the cluster
`occurred. If no other seizures were recorded for that seizure type during the Treatment Phase,
`’the value was to be set to number of seizures associated with the report of the cluster seizure.
`
`There were to be approximately 80 sites from 9 countries in this trial, and it was planned to pool sites
`by region for analysis purposes. Sites were to be grouped into Eastern Europe (Hungary, Lithuania,
`Poland), Western Europe (France, Germany, Sweden, Switzerland, United Kingdom), Northeastern
`U.S., Southeastern US, and Western US.
`
`The pair-wise comparison of the SPM 927 dose group versus placebo for reduction in seizure
`frequency described above was to be performed following a pre-defined hierarchical sequential
`rejective testing procedure. All null hypotheses were to be defined as no difference between the
`SPM 927 dose group and placebo and were to be tested using a two-sided test at the 5% level of
`significance. The hierarchical testing procedure was to start with the highest SPM 927 dose
`versus placebo. If the test was not statistically significant, the procedure was to stop, and no
`groups were to be declared different frOm placebo. If the test was statistically significant, the
`dose group was to be considered different from placebo and the procedure was to continue with
`the next highest dose. The procedure was to be repeated until the first time a test was not
`statistically significant. This testing procedure is considered a closed testing procedure and no
`adjustment of the significance level was to be necessary. Any comparisons between SPM 927
`dose groups were to be considered exploratory and tested at the 5% significance level without
`multiplicity adjustment. In addition, a corresponding two-sided 95% confidence interval for the
`treatment effect was to be calculated for each pair-wise comparison.
`
`2) Response to treatment was to be based on the percent change in seizure frequency. Subjects with
`at least a 50% reduction in seizure frequency were to be categorized as a responder. The responder
`rate between each treatment and placebo was to be analyzed using logistic regression with
`treatment and region as factors.
`
`Other Secondary Efficacy Variables
`- Reduction in seizure frequency per 4 weeks from baseline to treatment phase, defined
`as titration and maintenance phase.
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`- Response to treatment of at least 50% fiom baseline to treatment phase, defined as
`titration and maintenance phase.
`- Response to treatment of at least 75% from baseline to maintenance phase.
`- Response to treatment of at least 75% from baseline to treatment phase, defined as
`titration and maintenance phase.
`- Change in seizure frequency from baseline to maintenance phase differentiated by
`seizure type (i.e. simple partial seizures, complex partial seizures, partial seizures with
`secondary generalization).
`- Change in seizure frequency from baseline to treatment phase, defined as titration and
`maintenance phase, differentiated by seizure type (i.e. simple partial seizures, complex
`partial seizures, partial seizures with secondary generalization).
`- Achievement of “Seizure Free” Status (Yes/No).
`“Seizure free” with respect to this trial means that no seizure, of the type counted in this
`trial, occurs during the maintenance phase.
`(Status of subjects who discontinued the trial before reaching 28 days of maintenance
`phase was to be assumed not to be seizure free.)
`- Proportion of seizure free days during maintenance phase.
`- Clinical Global Impression of Change at the end of titration and maintenance phases.
`- Changes1n the assessment of Quality of Life1n Epilepsy from baseline to the end of
`titration and maintenance phases [only for the subpopulation of subjects from United
`Kingdom (UK) and United States of America (USA)].
`
`Statistical Analysis of Secondary Variables
`Selected important secondary efficacy variables were to be analyzed using methods similar to the
`ANCOVA and logistic regression methods described previously. For the remaining efficacy
`variables and all safety variables, descriptive statistics by treatment group were to be presented.
`
`Definition of Analysis Sets
`The primary analysis set for the analysis of efficacy data was to be the Full Analysis Set (FAS),
`which was to include all subjects who were randomized, received at least one dose of trial
`medication, and had at least one post-baseline efficacy assessment. The Per Protocol Set (PPS)
`was to be defined during blind review, and include the subset of subjects from the FAS who had
`seizure frequency data in the maintenance phase and did not have major protocol violations.
`
`Analysis of variables using t