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`CENTER FOR DRUG EVALUATION AND RESEARCH
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`APPLICATION NUMBER: 020717
`
`STATISTICAL REVIEW18)
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`CENTER FOR DRUG EVALUATION AND RESEARCH
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`APPLICATION NUMBER: 020717
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`STATISTICAL REVIEW18)
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`Statistical Review and Evaluation
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`w
`# 20
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`OCT 3 l
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`Wail
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`W: NDA Vols dated December 27, 1996 by sponsor’s cover letter
`
`MW; Robert Rappaport, MD, RFD-120
`
`W T
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`he sponsor has submitted two US multicenter, placebo-controlled, double-blind, parallel trials of
`modalfinil for the treatment of excessive daytime sleepiness (EDS) associated with narcolepsy.
`Although 4 other European trials have been submitted, this review covers only the US studies 301
`and 302.
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`'n
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`lin'cl
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`n
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`i
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`Both trials had double-blind treatment periods of 9 weeks. Treatment arms were placebo, 200
`mg/d, and 400 mg/d. Primary endpints were the MWT (Maintenance of Wakefulness Test) and
`the CGI-C (Clinical Global Impression of Change). The MWT was given 4 times during each visit
`(visits at baseline and at weeks 3, 6, and 9). The average ofthe 4 observations was used as the
`unit of analysis for the visit. The maximum time to fall asleep was set at 20 minutes.
`Secondary endpoints were the MSLT (Multiple Sleep Latency Test), the Epworth Sleepiness
`Scale (E88), and the Steer Clear Performance Test (SCPT).
`
`This review focuses on the "efficacy-evaluable“ patients: those who took medication at least once
`and who had at least one post-baseline observation for bath the MWT and the CGI-C.
`
`The primary analysis was ANCOVA for MWT (baseline average MWT as the covariate along
`with study site as a factor) and CMH for the CGI-C using study site and baseline CGI-S as strata.
`
`The trials were designed so that 95 patients/group would be sufiicient to achieve 80% power to
`detect a difference of 4.0 change fi'om baseline units compared to placebo.
`
`Results
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`Patient characteristics were well-balanced at baseline. Since the design and results of both
`studies are nearly identical, they will be discussed together.
`
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`MWT (All tables come from the sponsor’s NDA submission)
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`Table 1 displays the number of patients at each visit week of the study for the eficacy-evaluable
`subset. There does not appear to be a significant problem with dropouts. Table 2 displays the
`entire set of results for both trials for this patient subset. See Figure l for graphical displays of
`each trial’s treatment means over time. In both studies, both doses were statistically significantly
`difl‘erent fi'om placebo for both primary endpoints (p<.01 or less). Part of this treatment difi‘erence
`was due to the percentages of patients who remained awake for the full 20 minutes.Table 3
`displays the percentage of patients in each treatment group who stayed awake for a given number
`(0, 1, 2, 3, or 4) of 20 minute periods. At endpoint in both studies, approximately 80% of the
`placebo patients fell asleep within 20 minutes, whereas only 55% ofthe modafinil patients did.
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`I
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`CGI-C
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`Table 4 displays the distribution of CGI-C scores in both studies. Both studies seem to show that
`a large part of the treatment effect comes from the category “much improved” in the 400 mg/d
`group. Table 5 displays the percentage of patients who “improved”, while Figure 2 displays a bar
`chart of the percentage of patients who improved over time. P-values for comparisons to
`placebo are clearly significant in both studies.
`
`Qanslusicn
`
`The sponsor has submitted two clinical trials showing statistical evidence that modafinil is more
`efi‘ective than placebo in prolonging wakefulness. There is no evidence that 400 mg/d is more
`efi‘ective than 200 mg/d.
`/S/
`
`,3,
`
`David Hoberrnan, Ph.D.
`Mathematical Statistician
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`‘
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`_
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`/S/
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`Concur: Dr. Sahlroot W 13/75/77
`cc.
`Dr. Chi 9‘01“ ‘47
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`/S/
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`HFD- l 20/Dr. Rappaport
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`$13-120W“s.W
`APPEARS THIS WAY ON ORIGINAL
`HFDo344/Dr. Barton
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`RFD-7 l 0/Dr. Chi
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`HFD-710Dr. Sahlroot
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`HFD-710/Dr. Hoberman
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`TABLE 1
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`Patient Disposition by Visit
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`Study ClSJSaBOl/NAIUS and Study ClSSSa/JOZINA/US (EI'fiucy-Evnluable)
`
`301/302
`Combined
`
`
`
`< I
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`-
`
`Source:
`
`Abbreviations:
`mg/d = milligram per day modnfinil
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`Table FollowingText l.l.
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`TABLE 2
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`FIGURE 1
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`Study C1538a/301/NA/US
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`I ‘00 mg uaaalinil
`v 200 mg Madonna
`0 Placebo
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`**
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`Week 6
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`Visn"
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`Week 9
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`Endpoint
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`"
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`'0
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`5“
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`
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`Week 3
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`0
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`Baseline
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`Study C1538a/302/NA/US
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`16
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`.
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`man(s2SEM)uwrSLEEPminor 0
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`10
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`Baseline
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`Week 3
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`Week 6
`VISIT
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`Week 9
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`Endpoint
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`in narcolepsy
`Mean (1 2 SEM) MWT Sleep Latency versus visit
`patients receiving once daily oral doses of 400 mg/d modafinil, 200
`mg/d modafinil, or placebo for 9 weeks.
`
`
`
`a
`—-—-———f
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`_
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`--
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`K
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`*
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`TABLE 3
`
`Summary of MWT Resul:\s-—- Percentage of Patients Who
`
`Stayed Awake
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`Study CtsssmOIINA/US and Study ClSSBa/JOZ/NA/US (Efficacy-Evaluable)
`
`mmm- saw-m
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`
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`
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`Study 301/302 Combined
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`Source:
`Table Following Text l0.0.
`‘
`Primary analysis at Endpoint: Significantly different from placebo - 400 mg/d modat'tnil p<0.05 (30]. 302);
`- 200 mg/d modafinil p<0.05 (30l. 302). Note: 30l/302 combined analysis not done.
`Note: Efficacy-Evaluable patients are those who received at least 1 dose of study medication and had at least
`I post-baseline assessment for both MWT and CGl—C. Only patients with a positive response at all four tests
`are included. Endpoint is defined based on average of four tests.
`A value of 0 indicates that a patient stayed awake'for none of the 4 MWT assessments While a value of
`4 indicates a patient stayed awake for 20 minutes or longer for all of the 4 MWT assessments on a given day.
`Abbreviations:
`CGl-C = Clinical Global Impression of Change; mg/d = milligram per day modafinil; MWT 8 Maintenance of
`Wakefulness Test; N = number of patients.
`
`APPEARS THIS WAY 0N ORIGINAL
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`TABLE 4
`
`Summary of CGI-C — Endpoint" Values (Number [%] in
`Each Category)
`Study ClS38a/301/NA/US and Study C1538af302/NA/US [EmucyEvaluable]
`
`
`
`
`—-m-
`—-m-
`—m
`
` m.—
`
`30 l 002
`
` Source: Table Following Text I LO.
`'
`Primary analysis at Endpoint: Significantly different from placebo - 400 mg/d modafinil p<0.00l (30!.
`301/302), p=0.02 (302); - 200 mg/d modafinil p<0.00l (301. 301/302). p=0.01 (302).
`Efficacy-Evaluable patients an: those Mia min at last I dos: ofnudy mediation and Md at In! I ”Wine
`Note:
`asmsmem for both MWT and CGl-C.
`Abbreviations:
`.
`-
`CGl-C = Clinical Global lmprssion of Change; mud - milligram on day Marni“; MWT - Maintenance othefulnss Tat;
`N - number of patients.
`>
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`TABLE 5
`
`Summary of CGI-C Results —- Nurnber (%) of Patients Who
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`Improved
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`Study ClSJ8n/301/NA/US and Study CIS38a/302/NA/US (Efficacy-Evaluable)
` Treatment
`Grou -
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`36 (40)
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`62 (67)
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`66 (80)
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`33 (38)
`
`4s (55)
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`6o (70)
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`69 (39)
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`35 (40)
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`6| (66)
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`63 (78)
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`38 (44)
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`55 (71)
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`51 (62)
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`73 (42)
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`32 (37)
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`6o (65)
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`6o (74)
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`46 (58)
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`5| (61)
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`64 (38)
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`107 (6|)
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`Il6(68)
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`I06(62)
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`“4 70
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`34 (37)
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`‘
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`6t (64)
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`62 (72)
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`33 (3s)
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`4s (58)
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`52 (60)
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`67 (37)
`'
`[09(61)
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`
`IIIIIIIII
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`
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`Placebo
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`200 mg/d
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`400 mg/d
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`200 mg/d
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`400 mg/d
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`Placebo
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`200mg/d
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`
`
`301/302
`Combined
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`
`
`
`
`I26 75
`400m_d
`Table Following Text “.0.
`Primary analysis at Endpoint: Significantly different from placebo - 400 myd modnftnil p<0.00l
`(301. 301/302). p<0.0l (302); - 200 mg/d modafmil p<0.00l (301, 301/302), p<0.01 (302).
`’ Efficacy-Evaluable patients are those who received at least I dose of study medication and had at
`least I post-baseline assessment for both MWT and CGl-C.
`Abbreviations:
`
`Source:
`’
`
`Note:
`
`CGl-C = Clinical Global Impression of Change; ngd = milligram per day modaflnil; MWT = Maintenance of
`Wakefulness Test.
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`‘ 4-‘......‘_.-__'....:.._._- _,_,
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`. .J c
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`FIGURE 2
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`Study C1538a/301/NA/US
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`Week 9
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`Endpoint
`
`Week 3
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`Study C1538a/302/NA/US
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`" A
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`90"!
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`Percentage of patients in each dose group at each visit whose CGI-C Scores
`' Improved.
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