CENTER FOR DRUG EVALUATION AND
`RESEARCH
`’
`
`APPLICA TION NUMBER:
`
`2 1 -92 6
`
`STATISTICAL REVIEW! SQ
`
`

`

`
`
`U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES
`FOOD AND DRUG ADMINISTRATION
`CENTER FOR DRUG EVALUATION AND RESEARCH
`OFFICE OF PHARMACOEPIDEMIOLOGY AND STATISTICAL SCIENCE
`OFFICE OF BIOSTATISTICS
`
`STATISTICAL REVIEW AND EVALUATION
`
`Clinical Studies
`
`NDA/Serial Number:
`
`21-926/000
`
`Drug Name:
`
`Indication:
`
`Applicant:
`Date:
`
`Review Priority: -
`
`Trexima ® (combination of sumatriptan 85mg
`and naproxen sodium 500 mg)
`
`Migraine
`
`Pozen
`
`August 5, 2005
`
`Standard
`
`Biometrics Division:
`
`Biometrics I (HFD 710)
`
`Statistical Reviewer:
`
`Kun He
`
`Concurring Reviewers:
`
`Kun Jin, , Ph.D.,Team Leader
`Kooros Mahjoob, Ph.D., Deputy Director
`
`Medical Division:
`
`Neuropharmacological Drug Products (HFD 120)
`
`Clinical Team:
`
`Ronald Farkas, M.D., Clinical RevieWer
`
`Eric Bastings, M.D., Team Leader
`
`Russell Katz, M.D., Director
`
`Project Manager:
`
`Lana Chen, R. Ph.
`
`Keywords: Migraine, CMH test
`
`

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`NDA 21-926
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`
`TABLE OF CONTENTS
`
`1.
`
`Executive Summary ...........................................................................................................................................3
`
`1.1 Conclusions and Recommendations.................................................................................................................. 3
`
`1.2 Brief Overview of Clinical Studies..................................................................................................................... 3
`
`1.3 Statistical Issues and Findings .......................................................................................................................... 5
`
`2. Introduction ............................................................................................................................................................. 6
`
`2.1 Overview ............................................................................................................................................................. 6
`
`2.2 Data Sources ...................................................................................................................................................... 7
`
`3. Statistical Evaluation ...............................................................................................................................................7
`
`3.1 Evaluation ofEfficacy ....................................................................................................................................... 7
`3.1.1 Study MT400-301 ....................................................................................................................................... 7
`3.1.1.1 Objective ofStudy.............................................................................................................................
`...7
`3.1.1.2 Study Design .....................................................................................................................................
`-...7
`3.1.1.3 Efficacy Measures ..........................................................................................................................
`...8
`3.1.1.4 Statistical Analysis Plan ..................................................................................................................... , ..... 8
`3.1.1.5 Study Population ...................................................................................................................................... 8
`
`3.1.1.6 Applicant’s Efficacy Results ........................................................................................................... 12
`3.1.2 Study MT400-302............................- ......................................................................................................... 14
`3.1.2.1 Objective of Study..............................................,.................................................................................... 14
`
`3.1.2.2 Study Design ............................................................................................................................. 14
`3.1.2.3 Efficacy Measures .............................................................................................. '. ................................... 14
`3.1.2.4 Statistical Analysis Plan ......................................................................................................................... 14
`3.1.2.5 Study Population .................................................................................................................................... 14
`3.1.2.6 Applicant’s Efficacy Results .................................................................................................................. 18
`3.1.3 Reviewer’s Analysis .................................................................................................................................. 19
`Analysis on Nausea ............................................................................................................................................ 20
`
`
`
`3.2 Evaluation ofSafety......................................................................................................................................... 21
`
`4. Findings in Special/Subgroup Populations ..........................................................................................................22
`
`4.1 Gender, Age, and Race .................................................................................................................................... 22
`
`4.2 Other Special/Subgroup Populations .............................................................................................................. 23
`
`5. Summary and Conclusions....................................................................................................................................23
`
`5.1 Statistical Issues and Collective Evidence ....................................................................................................... 23
`
`5.2 Conclusions and Recommendations................................................................................................................ 25
`
`

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`NDA 21-926
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`
`Statistical Review and Evaluation
`
`1. Executive Summary
`
`1.1 Conclusions and Recommendations
`
`The data and analyses based on both Studies 301 and 302 indicated that Trexima was statistically
`significantly superior to placebo for 2-hour pain relief, 2-hour photophobia—free and 2-hour
`phonophobia-free. Trexima was statistically significantly superior to placebo for 2—hour nausea—free
`in Study 302. Trexima was also statistically significantly superior to the components for sustained
`pain free.
`
`_ 1.2 Brief Overview of Clinical Studies
`
`The submission had two identical randomized, double-blind, parallel-group, placebo and active
`controlled single attack studies in patients with moderate or severe migraine headache. Both studies
`compared a single Trexima tablet with placebo for relief ofmigraine pain and associated symptoms
`at 2 hours and compared Trexima to the individual active components (85 mg sumatriptan RT and
`500 mg naproxen sodium) for sustained pain relief through 24 hours. Each study enrolled
`approximately 1600 patients to each of the four treatment groups in a 1:1:121 ratio at approximately
`60 centers in the United States.
`
`The primary endpoints for the superiority comparison between Trexima and placebo are at two hours
`post-dose for pain relief (no or mild pain), incidence ofphotophobia, incidence ofphonophobia, and
`incidence of nausea.
`
`The primary endpoints for the superiority comparisons between Trexima and its individual
`components, sumatriptan and naproxen sodium, are sustained pain-free at 24 hours, which is defined
`as no pain at 2 hours and no relapse of pain (to mild, moderate or severe) and no use of rescue
`medication during the 24-hour period after dosing.
`
`The primary analyses forthe superiority comparisons between Trexima and placebo are Cochran—
`Mantel—Haenszel (CMH) tests with two outcome categories and with pooled investigator sites as
`strata, which applies to endpoints of pain relief, incidence of photophobia, and incidence of
`phonophobia for both Studies. The primary analysis for the superiority comparison between Trexima
`and placebo for incidence of nausea is a Cochran-Mantel-Haenszel (CMH) test with two outcome
`categories and with pooled investigator sites as strata for Study 301, and is a logistic regression with
`the baseline symptom and pooled investigator sites as covariates for Study 302.
`
`

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`NDA 21-926
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`
`For both Studies, the primary analyses for the superiority comparisons between Trexima and its
`individual components, sumatriptan and naproxen sodium, are a Cochran-Mantel-Haenszel (CMH)
`test with two outcome categories and with pooled investigator sites as strata, which applies to
`endpoints of sustained pain-free at 24 hours. Pairwise comparisons of sumatriptan to placebo and of
`naproxen sodium to placebo are also done for pain relief at 2 hours, using a CMH test.
`
`Results of primary analyses are presented in following tables.
`
`Table 1.2.1 Study 301: Primary Efficacy Analyses at 2 Hours (ITT)
`
`Pain Relief — n (%)
`
`Photophobia-free — n (%)
`
`Phonophobia-free — n (%)
`
`Nausea-free — n (%)
`
`Trexima
`N = 362
`
`207 (57)
`
`180 (50)
`
`204 (56)
`
`237 (65)
`
`Placebo
`N = 382
`
`109 (29)
`
`122 (32)
`
`128 (34)
`
`244 (64)
`
`p-Value
`
`<0.001
`
`<0.001
`
`<0.001
`
`0.71 1
`
`
`
`
`
`
`Table 1.2.2 Study 301: Primary Efficacy Analyses at 24 Hours (ITT)
`
`
`
`
`
`
`
`
`
`
`
`
`
`Trexima
`N = 362
`
`Sustained Pain-Free — n (%)
`
`83 (23)
`
`Sumatriptan
`N = 362
`
`Naproxen
`Sodium
`N = 364
`
`
`
`
`
`51 (14)
`
`37 (10)
`
`25 ('7)
`
`Table 1.2.3 Study 302: Primary Efficacy Analyses at 2 Hours (ITT)
`
`——-—
`——__
`
`
`
`
`
`
`analysis adjusted for baselinc nausea
`
`
`
`

`

`NDA 21-926
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`
`Table 1.2.4 Study 302: Primary Efficacy Analyses at 24 Hours (ITT)
`
`Trexima
`
`
`
`
`Sumatriptan
`Naproxen
`N = 364
`
`N = 361
`Sodium
`
`
`N=356
`
`
`
`
`
`
`
`Sustained Pain-Free — n (%)
`
`90 (25) _
`
`59 ( l 6)
`
`37 ( 10)
`
`30 (8)
`
`1.3 Statistical Issues and Findings
`
`An imbalance in incidence of nausea at baseline between Trexima and placebo were observed for
`both Studies 301 and 302, which might affect the evaluation of treatment differences of the 2-hour
`post-dose incidence of nausea. Statistical analysis on nausea-free at 2 hours is not significant for
`Study 301 using a CMH test stratified by pooled sites, and is significant for Study 302 using a
`logistic regression adjusted for baseline. Numerically, subjects treated with Trexima had a higher
`nausea-free rate at 2, 3 and 4 hours compared to placebo in both studies.
`
`on Original
`
`

`

`NDA 21-926
`
`2. Introduction
`
`2.1 Overview
`
`6 of25
`
`Migraine, as defined by the International Headache Society, is a chronic paroxysmal Disorder. A
`migraine attack is characterized by intense unilateral throbbing headache pain, which is accompanied
`by one or more secondary symptoms including nausea, sensitivity to light and sound, and
`occasionally vomiting. In about 10% of cases, migraine is associated with neurological symptoms
`known as aura, which are characterized by visual, sensory, speech, or motor dysfunction. Clinical
`disabilities are usually significant, with many patients requiring a period of bed rest. An individual
`attack lasts anywhere from 4 — 72 hours. Surveys found that patients want an acute treatment for
`migraine that provides: (a) rapid onset of pain relief, (b) fi'eedom fiom pain, (0) no recurrence of
`headache and (d) absence of adverse effects. The International Headache Society Clinical Trial
`Committee has proposed that the pain—free response at 2 hours after dosing provides the best measure
`ofrapidity ofrelief and acute freedom fiom pain while sustained pain-free is the preferred composite
`measure denoting freedom from pain and lack of relapse of headache.
`
`Trexirna tablets, a combination product, contain sumatriptan succinate and naproxen sodium and are
`intended for the acute treatment of migraine with or without aura in adults 18 years of age or older.
`Sumatriptan succinate (hereafter sumatriptan), developed by Glaxo and currently marketed in the
`US. by GlaxoSmithKline under the trade name Imitrex (NDA 20-132), is indicated for the acute
`treatment of migraine attacks. Naproxen sodium, a nonsteroidal anti—inflammatory agent (NSAID)
`developed by Syntex and currently marketed in the US. by Roche Pharmaceuticals under the trade
`name Anaprox (NDA 18-164), is indicated for the treatment of rheumatoid arthritis, osteoarthritis,
`ankylosing spondylitis, juvenile arthritis, tendonitis, bursitis, acute gout, and for the management of
`pain and primary dysmenorrhea.
`
`An initial IND (#60,669) was submitted on July 26, 2000 covering the administration ofsumatriptan
`and naproxen sodium marketed products in combination. The initial proofof-concept study (MT400-
`204), using over-encapsulated Imitrex (sumatriptan succinate) 50 mg tablets and naproxen sodium
`500 mg tablets was conducted under this IND. A second IND (#68,436) was submitted on December
`18, 2003 to conduct the clinical studies on the fixed dose combination selected.
`
`The pivotal efficacy program in NDA 21-926 was comprised of two identical randomized, double-
`blind, parallel—group, placebo and active controlled single attack studies in patients with moderate or
`severe migraine headache. Both studies compared a single Trexirna tablet with placebo for relief of
`migraine pain and associated symptoms at 2 hours and compared Trexirna to the individual active
`components (85 mg sumatriptan RT and 500 mg naproxen sodium) for sustained pain reliefthrough
`24 hours. Each study enrolled approximately 1600 patients to each of the four treatment groups in a
`1:1:1:l ratio at approximately 60 centers in the United States.
`
`

`

`7 of 25
`
`NDA 21-926?
`
`2.2 Data Sources
`
`\\Cdsesub1\n21926\N 000\2005-O8-05
`
`3. Statistical Evaluation
`
`3.1 Evaluation of Efficacy
`
`3.1.1 Study MT400-301
`
`3.1.1.1 Objective of Study
`
`The objectives of the study were to demonstrate the superiority of Trexima (combination of
`sumatn'ptan as the succinate 85 mg and naproxen sodium 500 mg) versus placebo in the acute
`treatment of migraine, to demonstrate the superiority of Trexima versus the individual components
`(sumatriptan as the succinate 85 mg and naproxen sodium 500 mg), and to evaluate the safety of
`Trexima.
`
`3.1.1.2 Study Design
`
`This was a randomized, double-blind, parallel group, placebo-controlled, single dose multicenter
`study conducted in the US. Subjects were randomized in a ratio of 1:1:1:1 to receive Trexima,
`sumatriptan 85 mg, naproxen sodium 500 mg, or placebo orally.
`
`The study consisted of a screening visit, at home treatment of a single migraine attack and a follow—
`up Visit 1-5 days following treatment. Subjects had a baseline safety assessment performed at the
`screening Visit including a review ofmedical history, review ofmigraine treatment history, physical
`examination, clinical laboratory tests, electrocardiogram (ECG), and a pregnancy test for females of
`childbearing potential. Blinded study drug was dispensed to eligible subjects at the end of the
`screening visit according to the randomization schedule provided by POZEN. When the subject’s
`next migraine attack of moderate or severe intensity occurred, the subject reviewed the eligibility
`checklist and ascertained whether he/she continued to meet the eligibility criteria for use of study
`drug. Subjects eligible for treatment completed pain, clinical disability, and symptom (photophobia,
`phonophobia, nausea, vomiting) assessments on a diary card immediately prior to taking study drug.
`After taking the study drug, the subject completed assessments every 30 minutes for the first 2 hours,
`hourly from 2-4 hours, and then hourly while awake for the next 20 hours. Subjects were allowed to
`take rescue medication, if necessary, no sooner than 2 hours after taking the study drug. A Health
`Outcomes Productivity Assessment and The Patient Perception ofMigraine Questionnaire (PPMQ)
`were completed 24 hours post-dosing. At the follow-up visit, safety assessments, diary review and
`concomitant medications review were conducted.
`
`The main inclusion criteria is that subjects were males or non-pregnant, non-lactating females 18-65
`
`

`

`NDA 21-926
`
`8 of 25
`
`years of age, had a demonstrated history (at least 6 months) of migraine headaches according to the
`International Headache Society (IHS) criteria 1.1 or 1.2, had their first migraine prior to age 50, and
`had an average migraine headache fiequency of 2-6 moderate or severe attacks per month in the
`previous three months.
`
`3.1.1.3 Efficacy Measures
`
`Efficacy evaluations included diary recordings ofpain intensity and clinical disability (each rated on
`a scale of 0-3); symptoms of photophobia, phonophobia, nausea and vomiting, rated as present or
`absent; and use of rescue medication. In addition, subject Satisfaction Questionnaires were
`completed for previous migraine treatment and for study drug, and a Productivity Assessment for
`work and non—work activities during the treatment period was completed.
`
`The primary endpoints for the superiority comparison between Trexima and placebo are at two hours
`post-dose for pain relief (no or mild pain), incidence ofphotophobia, incidence ofphonophobia, and
`incidence of nausea.
`
`The primary endpoints for the superiority comparisons between Trexima and its individual
`components, sumatriptan and naproxen sodium, are sustained pain-free at 24 hours, which is defined
`as no pain at 2 hours and no relapse of pain (to mild, moderate or severe) and no use of rescue
`medication during the 24-hour period after dosing.
`
`3.1.1.4 Statistical Analysis Plan
`
`All primary analyses would be performed using the Last Observation Carried Forward (LOCF)
`approach'based on the Intent-to-treat (IT-T) population.
`
`The primary analyses for the superiority comparison between Trexima and placebo are Cochran-
`Mantel-Haenszel (CMH) tests with two outcome categories and with pooled investigator sites as
`strata, which applies to endpoints ofpain relief, incidence ofphotophobia, incidence ofphonophobia,
`and incidence of nausea.
`
`The primary analyses for the superiority comparisons between Trexima and its individual
`components, sumatriptan and naproxen sodium, are a CMH test with two outcome categories and
`with pooled investigator sites as strata, which applies to endpoints of sustained pain-free at 24 hours.
`Pairwise comparisons of sumatriptan to placebo and ofnaproxen sodium to placebo are also done for
`pain relief at 2 hours, using a CMH test.
`
`3.1.1.5 Study Population
`
`A total of 1875 subjects were screened and 1736 were randomized. Ofthese, 1495 treated a migraine
`with study drug, and 1475 returned diary cards. Fourteen hundred seventy (1470) subjects completed
`
`

`

`NDA 21-926
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`
`at least one post-treatment diary card assessment and treated their migraine as instructed, While it
`was moderate or severe; these 1470 subjects comprised the. efficacy lTT population. Twenty-one
`subjects had a major protocol Violation; thus, there were 1449 subjects in the per protocol
`population. The following table (adapted from Study report, p53 in MT400-30l) presents the patient
`disposition information.
`
`Table 3.1.1.5.1 Patient Disposition
`
`Trexima
`
`Naproxen
`Sodium
`
`Placebo
`
`Total
`
`
`
`
`
`
`
`
`
`
`
`——_—
`
`T1eated
`(SafetyPovulatiom --- ”95
`
`
`Efficacy Inltent~toeT1eat
`362
`n 62
`1470
`Population
`J
`
`PerProtocolPopulati0112— 355 -:— 1449
`
`
`
`
`
`5
`
`Includes all subjects who ingested study drug, rec01ded moderate or seve1e pain at baseline and lecorded
`u
`u
`.
`.
`.
`at least one post-dose pain assessment
`‘Excludes all subjects With a major protocol Violation
`
`The demographic characteristics of the study population at screening are summarized in Table
`3.1.1.5.2 (adapted from Study report, p57).
`
`Appears This Way
`On Original
`
`

`

`NDA 21-926
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`10 of 25
`
`Table 3.1.1.5.2 Demographic and Baseline Information (Safety)
`
`N = 367
`
`N = 370
`
`
`
`Sodium
`N = 371
`
`
`
`N = 387
`
`
`
`-—_—_—
`_—__-—
`———-—
`——_——_
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Latino
`
`Latino
`
`__-_--
`
`—-_-_-_-—
`——_———
`—__—__
`——————
`___—-__
`—_—-_—
`—‘-—__-_—
`——————
`_——-_-_—
`———-—mm-
`___—
`No
`______
`___-——
`—_—__—
`__—__-
`—_____
`—_-———
`Age Category -
`0.280
`136(37)
`139(38)
`125(32) _
`193 (52)
`192 ('52)
`197(54)
`230 (59) _
`——__—_
`“___———
`————_—
`—_-_—_
`——__——
`_—_———
`_—————
`——___—
`——————
`—__-——
`
`Min — Max
`94-0 — 308
`95.0 — 322 __—
`
`
`(vears)
`
`
`
`
`
`
`
`
`
`

`

`NDA 21-926
`
`11 of 25
`
`A summary of migraine history at screening is presented in Table 3.1.1.5.3 (adapted from Study
`report, p5 8).
`
`Table 3.1.1.5.3 Migraine History at Screening (Safety)
`
`Trexima
`N = 367
`
`
`
`
`
`Migraine Characteristics
`at Screening — n (%)
`
`Sumatriptan
`N = 370
`
`Naproxen
`Sodium
`N = 371
`
`
`
`
`
`
`
`
`
`Placebo
`N = 387
`
`
`
`
`
`
`
`
`
`
`
`
`
`27222722
`
`16
`
`272772
`2777722
`22772
`227222 -- 27722
`227222
`22722
`
`Migraine Attack (years)
`
`--
`
`27272222
`
`22
`
`
`
`
`
`
`
`0—58
`
`
`
`
`
`Baseline characteristics of the migraine treated with study drug are summarized in Table 3.1 .l .5.4
`(adapted fiom Study report, p59). A difference was noted for unilateral pain, with 66% of subjects
`treated with Trexima indicating unilateral pain vs. 70% to 75% of the other treatment groups with
`unilateral pain. A smaller percent of subjects in the Trexima treatment group as compared to the
`other treatment groups, had aura at baseline (19% vs. 23% to 26%). There appeared to be a baseline
`imbalance in the incidence ofnausea with a greater incidence of subjects treated with Trexima with
`nausea compared to the other treatment groups (56% vs. 48% to 49%).
`
`Appears This Way
`On Original
`
`

`

`NDA 21-926
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`12 of 25
`
`Table 3.1.1.5.4 Baseline Characteristics of the Treated Migraine (ITT)
`
`
`
` Characteristic
`n (%)
`Trexima
`
`
`
`
`
`
`Placebo
`N = 382
`
`p—Value
`
`2“
`
`Photophobia
`
`_300(83)-302(83)_301(83)_3lO(8l)
`
`0.857
`
`Pain Only on 1 Side of
`the Head‘
`
`Pulsating, Throbbing or
`Pounding
`
`238 (66)
`
`272 (75)
`
`253 (70)
`
`277 (73)
`
`0.044
`
`326 (90)
`
`329 (91)
`
`'
`
`330 (91)
`
`354 (93)
`
`0.529
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`314 (86)
`326 (90)
`316 (87)
`Worsens with Activity
`
`For pain severity, none and mild were not included in the analysis.
`2 One subject in the Trexima group did not answer the unilateral pain question.
`
`344 (90)
`'
`
`0.220
`
`
`3.1.1.6 Applicant’s Efficacy Results
`
`The primary efficacy analyses for the superiority comparison between Trexima and placebo are
`CMH tests stratified by the pooled sites. The results are presented in the following table (adapted
`from Study report, p60).
`
`

`

`NDA 21-926
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`13 of 25
`
`Table 3.1.1.6.1 Primary Efficacy Analyses at 2 Hours (ITT)
`
`
`
`
`
`Pain Relief — n (%)
`
`Photophobia-free — n (%)p '
`
`'
`
`Phonophobia-free
`
`n (%)
`
`Nausea-free — n (%)
`
`Trexima
`N = 362
`
`207 (57)
`
`180 (50)
`
`204 (56)
`
`237 (65)
`
`Placebo
`N = 382
`
`109 (29)
`
`122 (32)
`
`128 (34)
`
`244 (64)
`
`p-Value
`
`<0.001
`
`<0.001
`
`<0.001
`
`0.711
`
`
`
`
`Pain relief was achieved at 2 hours post-dose by 57% of subjects taking Trexima and 29% of
`subjects taking placebo. The treatment difference was statistically significant (p<0.001).
`
`The percentages of subjects who were photophobia—free and phonophobia-free at 2 hours after dosing
`were significantly greater in the Trexima treatment group ( 50% and 56%, respectively) than in the
`placebo treatment group (32% and 34%, respectively) (p<0.001). At 2 hours post-dosing, there was
`no significant difference in the percentages of subjects receiving Trexima or placebo who were
`nausea-free (65% and 64%, respectively).
`
`The primary efficacy results for the superiority comparison between Trexima and its components are
`CMH tests stratified by the pooled sites. The results are presented in the following table (adapted
`from Study report, p62). In the Trexima treatment group, 23% of subjects had a sustained pain—free
`response at 24 hours, compared to 14% of subjects in the sumatriptan treatment group, and 10% in
`the naproxen sodium treatment group. Differences between the Trexima treatment group and each of
`the components were statistically significant (p<0.001).
`
`Table 3.1.1.6.2 Primary Efficacy Analyses at 24 Hours (ITT)
`
`Trexima
`
`N = 362
`
`Naproxen
`Sodium
`
`N = 364
`
`Placebo
`
`N = 382
`
`
`
`
`Sumatriptan
`N = 362
`
`
`
`
`.
`
`
`
`Sustained Pain-Free — n (%)
`83 (23)
`51 (14)
`37 (10)
`_ p- alue vs. Trexima
`' _— <0.001
`
`
`
`
`
`
`
`25 (7)
`<0.001
`
`
`

`

`NDA 21-926
`
`3.1.2 Study MT400-302
`
`3.1.2.1 Objective of Study
`
`14 of 25
`
`The objectives of the study were identical to Study 301 (see Section 3.1.1.1).
`
`3.1.2.2 Study Design
`
`The design was identical to Study 301 (see Section 3.1.1.2).
`
`3.1.2.3 Efficacy Measures
`
`The efficacy measures and endpoints were identical to Study 301 (see Section 3.1.1.3).
`
`3.1.2.4 Statistical Analysis Plan
`
`The statistical analysis plan was identical to Study 301 (see Section 3.1.1.4) except for analyzing
`nausea-free at 2—hour.
`'
`
`In the Statistical Analysis Plan dated March 21, 2005, the protocol stated that “If any of the baseline
`symptoms (i.e. pain, nausea, photophobia and phonophobia) suggest a treatment imbalance, as
`evidenced by a p—value of<0. 15 for overall treatment differences, then the primary analysis (Trexima
`versus placebo at 2 hours) for that symptom will be adjusted for baseline. Logistic Regression, with
`the baseline symptom and pooled investigator sites as covariates, will be done instead of the
`Cochran—Mantel-Haenszel test.”
`
`The applicant provided documents to indicate that the database was locked on March 29, 2005 and
`the study unblinded to treatment assignments on March 30, 2005. Therefore, the change was done
`prospectively.
`
`3.1.2.5 Study Population
`
`A total of 1768 subjects were screened and 1677 were randomized. Ofthese, 1461 treated a migraine
`with study drug, and 1444 returned diary cards. Fourteen hundred and forty-one (1441) subjects
`completed at least one post-treatment diary card assessment and treated their migraine as instructed,
`while it was moderate or severe; these 1441 subjects comprised the efficacy ITT population. Forty-
`eight subjects had a major protocol Violation; thus, there were 1393 subjects in the per protocol
`population. The following table (adapted from Study report, p52 in MT400-302) presents the patient
`disposition information.
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`Table 3.1.2.5.1 Patient Disposition
`
`Trexima
`
`Naproxen
`Sodium
`
`Placebo
`
`Total
`
`
`
`Treated
`(Safety Population)
`
`Efficacy Inltent-to-Treat
`Population
`
`364
`
`.,
`
`361
`
`-
`
`”6‘
`
`1441
`
`356
`
`360
`
`Includes all subjects who took study drug, recorded moderate or severe pain at baseline and recorded at
`least one post-dose pain assessment
`2Excludes all subjects with a major protocol violation and all subjects at site 355 (see Section 10.2)
`Source: Section 14.1.2
`
`The demographic characteristics of the study population at screening are summarized in Table
`3.1.2.5.2 (adapted from Study report, p56).
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`Appears This Way
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`NDA 21-926
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`Table 3.1.2.5.2 Demographic and Baseline Information (Safety)
`
`
`------Sodium
`_____—
`_————_
`___—_—
`__—
`“—_-_—
`
`Latino
`
`Latino
`
`351(96) -
`344(95)
`350 (96)
`351(95)
`Not Hispanicor
`-_—-__—
`——____
`___—__
`m“—
`_-_-———
`_—-_.--_—
`—-——_—
`——__—_
`—-__--
`—___—-
`____—_
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Min — Max
`
`Wei_ht (lb
`
`Mean (iSD)
`Median
`
`_———__
`__————
`—-———-
`__———-
`“___—
`-_———_
`—_——--
`“__————
`N ___—
`65.6(3.4) ___—
`Mean (iSD)
`
`Median
`65-0 ___-
`
`56-0-77-0 ___—
`
`___—
`
`370 ___—
`164.5 (41.0) ___—
`158 ___—
`X
`Min — Ma
`
`93—320 ___-
`
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`A summary of migraine history at screening is presented in Table 3.1.2.5.3 (adapted from Study
`report, p57).
`
`Table 3.1.2.5.3 Migraine History at Screening
`
`
`
`
`Migraine Characteristics
`at Screening — 11 (9’0)
`
`,
`
`Trexima
`
`N=370
`
`285 (77)
`
`
`
`Sumatriptan
`
`N=365
`
`267 (73)
`
`
`
`
`
`Naproxen
`Sodium
`
`N=361
`
`259 (72)
`
`45 (12)
`
`57 ( [6)
`
`421mm
`
`
`
`
`—--
`
`Migraine Attack (years)
`
`N
`
`370
`
`365
`
`361
`
`mu»
`mu .5
`
`
`
`
`
`Placebo
`
`II
`
`2
`
`b.) O\U-
`
`258 (71)
`
`57(16)
`
`50(14)
`
`365
`
`18.7 (12.5)
`
`|
`
`O
`
`5
`
`ON
`
`
`
`
`
`
`Baseline characteristics of the migraine treated with study drug are summarized in Table 3.1.2.5.4
`(adapted fi'om Study report, p58). No differences between groups was noted for baseline
`characteristics with the exception of incidence of nausea, with a greater incidence of nausea in
`subjects treated with Trexima, sumatriptan and naproxen compared to placebo (48%, 46%, 49% vs.
`41%, respectively). The degree of nausea imbalance precluded use of logistic regression over CMH
`for nausea.
`
`Appears This Way
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`Table 3.1.2.5.4 Baseline Characteristics of the Treated Migraine
`
`Trexima
`
`N = 364
`
`n (%)
`
`Painl
`
`Moderate Pain
`
`227 (62)
`
`232 (64)
`
`228 (64)
`
`227 (63)
`
`Severe Pain
`
`137 (3 8)
`
`129 (36)
`
`128 (36)
`
`133 (37)
`
`
`
`Photophobia
`
`Phonophobia
`
`Nausea
`
`Aura2
`
`Pain Only on 1 Side of
`the Head2
`
`Pulsating, Throbbing or
`Pounding2
`
`288 (79)
`
`296 (82)
`
`287 (81)
`
`286 (79)
`
`281 (77)
`
`286 (79)
`
`265 (74)
`
`278 (77)
`
`176 (48)
`
`167 (46')
`
`174 (49)
`
`149 (41)
`
`76 (21)
`
`86 (24)
`
`75 (21)
`
`86 (24)
`
`267 (73)
`
`255 (71)
`
`254 (71)
`
`253 (70)
`
`0.780
`
`0.509
`
`0.149
`
`0.791-
`
`322 (88)
`
`322 (89)
`
`321 (90)
`
`323 (90)
`
`0.963
`
`Worsens with Activity2
`
`312 (86)
`
`‘
`
`315 (87)
`
`313 (88)
`
`317 (88)
`
`0.744
`
`For pain severity, none and mild were not included in the analysis.
`2 One subject in the Trexima group did not answer the migraine characteristics questions.
`
`3.1.2.6 Applicant’s Efficacy Results
`
`The primary efficacy analyses for the superiority comparison between Trexima and placebo are
`CMH tests stratified by the pooled sites. The results are presented in the following table (adapted
`from Study report, p59).
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`Table 3.1.2.6.] Primary Efficacy Analyses at 2 Hours (ITT)
`
`_——_
`
`
`
`Pain Relief— n (%)
`
`Photophobia-Free — n (%)
`
`Phonophobia-Free — n (%)
`
`Nausea-Free' — n (%)
`
`237 (65)
`
`21 1 (5 8)
`
`223 (61)
`
`260 (71 )
`
`102 (28)
`
`131 (36)
`
`138 (38)
`
`233 (65)
`
`0.007
`
`analysis adjusted for baseline nausea
`
`Pain relief was achieved at 2 hours post-dose by 65% of subjects taking Trexima and 28% of
`subjects taking placebo. The treatment difference was statistically significant (p<0.001).
`
`The primary efficacy results for the superiority comparison between Trexima and its components are
`CMH tests stratified by the pooled sites. The results are presented in the following table (adapted
`from Study report, p60). In the Trexima treatment group, 25% of subjects had a sustained pain—free
`response at 24 hours, compared to 16% of subjects in the sumatriptan treatment group, and 10% in
`the naproxen sodium treatment group. Differences between the Trexima treatment group and each of
`the components were statistically significant (p<0.01).
`
`Table 3.1.2.6.2 Primary Efficacy Analyses at 24 Hours (ITT)
`
`
`
`Sumatriptan
`N = 361
`
`Naproxen
`Sodium
`N=356
`
`Sustained Pain-Free — n (%)
`
`90 (25)
`
`59 (16)
`
`37 (10)
`
`30 (8)
`
`3.1.3 Reviewer’s Analysis
`
`The reviewer validated the applicant’s analyses according to the protocols.
`
`There are many small sites in both studies. The primary analysis is a CMH test stratified by pooled
`sites. To check whether there is any impact caused by sites, a CMH test without stratification by sites
`is performed which gives p-value .0001 for both studies.
`
`The primary endpoint is based on a binary transformation on pain relief. To check whether there is
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`any impact using such transformation, a CMH test with pain relief’ s original 4-point scales gives p—
`value .0001 for both studies.
`
`For checking baseline balance of pain relief, a CMH test using original 4—point scales gives p-value
`.6479 for Study 301, and .8472 for Study 302, respectively.
`
`Analysis on Nausea
`
`For Study 301: The numbers and percentages for nausea flee at 2 hours are 237/362 (65.5%) for
`trexima group, and 244/3 82 (63.9%) for placebo group, respectively. P-value for nausea flee at 2
`hours, using a CMH test stratified by pooled site, is .7114. Since there are many small sites in this
`study, p-value using a CMH test without stratification by sites is .6494.
`
`The numbers and percentages for nausea flee at baseline are 1161/362 (44.5%) for trexima group,
`and 194/382 (50.8%) for placebo group, respectively. P-value for nausea flee at baseline using a
`CMH test is .0852. Adjusting for baseline, p-value using a logistic regression for nausea free at 2
`hours is .2301.
`
`The nausea incidence over time in subjects receiving Trexima is presented in Table 3.1.3.1. By 2
`hours, the incidence of nausea in subjects treated with Trexima is lower than that in subjects treated
`with placebo (35% and 36%, respectively).
`
`
`Table 3.1.3.1 Study 301: Incidence of Nausea over Time (ITT Population)
`H 0 U R S
`P O S T — D O S E
`—————————————————————————————————————————————————————————