`
`CENTER FOR DRUG EVALUATION AND
`
`RESEARCH
`
`APPLICATION NUMBER:
`
`21-450
`
`MEDICAL REVIEW
`
`

`

`Review and Evaluation of Clinical Data
`
`IND (Serial Number)
`Sponsor:
`Drug:
`Proposed Indication:
`Material Submitted:
`
`.
`
`Correspondence Date:
`Date Received 1 Agency:
`Date Review Completed
`Reviewer:
`
`I. Introduction
`
`21-450
`AstraZeneca
`Zomig (zolmitriptan) Nasal Spray
`Acute Migraine
`Labeling
`edr \CDSESUBlN2l450N 0002003-04-25
`
`April 25. 2003
`April 25, 2003
`May 7, 2003
`Kevin Prohaska, 0.0.
`
`In this document I review the proposed labeling for Zomig Nasal Spray 5.0 mg submitted by the Spenser
`on April 25, 2003. The sponsor states that the revised labeling encompasses all the recommended changes
`to labeling contained in the Approvable Letter dated December 19, 2002. Additionally they have clarified
`the proposed labeling where requested, added a few new details, and completely reformatted the patient
`information sheet in the question/answer format presently recommended by the Agency. The sponsor
`states they used Relpax label as a guide in their reformatting. A DDMAC consult has been requested to
`review the proposed patient information sheet. My recommended changes are highlighted in red.
`
`II.Proposed Professional Package Insert
`Rev 01/03
`SIC 23570.00
`
`1’
`
`'
`
`*1
`
`_——‘\
`
`

`

`
`
`23
`
`Page(s) Withheld
`
`§ 552(b)(4) Trade Secret / Confidential
`
`§ 552(b)(5) Deliberative Process
`
`4 § 552(b)(5) Draft Labeling
`
`

`

`
`
`Kevin Prohaska, D‘0., HFD-‘IZO Medical Review
`IND. 21-450 Zomig Nasal Spray 5.0 mg
`
`Page 25 of 25
`
`
`
`Rev 01/03
`
`Kevin Prohaska, DO.
`Medical Reviewer
`
`A. Oliva, M.D.
`
`APPEMS THIS WAY
`0N fiRiGifi'AL
`
`25
`
`

`

`
`
`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`
`Kevin Prohaska
`
`7/30/03 02:50:37 PM
`MEDICAL OFFICER
`
`Armando Oliva
`
`8/4/03 09:02:03 AM
`MEDICAL OFFICER
`
`
`
`

`

`Clinical Review Cover Sheet
`
`NDA:
`
`21—450
`
`Sponsor:
`Drug:
`Proposed Indication:
`Materials Submitted
`
`Correspondence Date:
`Date Review Completed:
`Division:
`
`AstraZeneca
`Zomig (zolmitriptan) Nasal Spray
`Acute Migraine
`Response to Approvable Letter
`(95er
`March 27, 2003
`May 1, 2003
`Neuropharmacological Drug
`Products
`
`Reviewer:
`
`Kevin Prohaska, D.0.
`
`APPWW W”; WAY
`vv:
`““ifi
`'ar‘l
`
`

`

` CLINICAL REVIEW NDA 21—450
`
`Table at Contents
`
`Table of Contents .....................................................................................................2
`
`Executive Summary .................................................................................................4
`
`1.
`
`Recommendations ................................................................................................. 5
`
`1.]
`
`1.]
`
`Recommendation on Approvability ............................................................. 5
`
`Recommendation on Phase 4 Studies and/or Risk Management Steps ....... 5
`
`2.
`
`Summary of Clinical Findings ............................................................................. 5
`
`1.1
`
`Brief Overview of Clinical Program ............................................................ 5
`
`2.2
`
`Efficacy ........................................................................................................ 6
`
`2.3
`
`Safety ...........................................................................................................7
`
`2.4
`
`Dosing .......................................................................................................... 8
`
`Clinical Review ......................................................................................................... 9
`
`1.
`
`Introduction and Background ............................................................................. 9
`
`1.1
`
`Important Milestones in Product Development (Updated) ........................ 10
`
`2.
`
`3.
`
`Description of Clinical Data and Sources ......................................................... 10
`
`Integrated Review of Efficacy ............................................................................ 11
`
`3.]
`
`Detailed Description of Trial 022 .............................................................. i 1
`
`3.2
`
`Efficacy Results, Interim Analysis of Trial 022 ........................................ 13
`
`3.2.1 Demographics and Migraine History ....................................................... 13
`3.2.2 Primary endpoint results ........................................................................... 14
`3.2.3 Secondary endpoint results ....................................................................... 15
`
`3.3
`
`Efficacy Conclusions ..........................7....................................................... l7
`
`4.
`
`Integrated Review of Safety ............................................................................... 19
`
`4.1
`
`Description of Patient Exposure ................................................................20
`
`Page 2 of31
`
`BESTPOSSIBLECOPY
`
`

`

` CLINICAL REVIEW NDA 21—450
`
`Safety Review Findings .............................................................................21
`
`423.1 Deaths ....................................................................................................... 21
`4.3.2 Serious Adverse Events ............................................................................ 22
`4.3.3 Withdrawals......................................... . .................................................... 22
`4.3.4 Common Adverse Events ......................................................................... 23
`4.3.5 Clinical Laboratories ................................................................................ 27
`
`Patient Demographics ................................................................................20
`
`!
`
`4.2
`
`4.3
`
`4.3.6 Vital Signs ................................................................................................ 27
`4.3.7 Electrocardiogram ................. . ................................................................ 27
`4.3.8 Nose and Throat Examination .................................................................. 27
`
`4.3.9 Post-Marketing Safety Data ..................................................................... 28
`
`4.4
`
`Summary of Critical Safety Findings and Limitations of Data ................. 28
`
`4.5
`
`Brief Statement of Safety Conclusions ......................................................29
`
`S.
`
`6.
`
`Dosing, Regimen, and Administration Issues ................................................... 29
`
`Final Conclusions and Recommendations ........................................................ 29
`
`6.1
`
`Conciusions ......................................................... ........................................29
`
`6.2
`
`Recommendations ...................................................................................... 30
`
`7.
`
`Appendix .............................................................................................................. 31
`
`Appendix 1: List of Tables ....................................................................................31
`
`AFPMRS THEE ‘iiil‘t'
`
`(iii @RiGii’ii‘tL
`
`BEST POSSIBIE 00??
`
`
`
`Page 3 of31
`
`

`

`CLINICAL REVIEW NDA 21-450
`
`
`
`Executive Summary Section
`
`Clinical Review for NBA 21-450
`
`ExeCutive Summaflg
`
`The sponsor is developing Zomig Nasal Spray (ZN S) 5.0. —-——————- mg for the treatment
`of acute migraine. The original NDA was Submitted on February 27, 2002. An Approvable
`Letter was issued December 19, 2002. This executive summary and review only covers the
`material submitted by the Sponsor in response to our Approvable Letter. My original review of
`the NDA submission can be found in DFS.
`
`The active moiety in Zomig Nasal Spray (ZNS), zolrnitriptan, is the same active moiety found in
`Zomig Tablets (2.5 and 5.0 mg) approved by the Agency on November 25, 1997 (NDA 20—768)
`for the acute treatment of migraine with and without aura in adults. Zolmitriptan is a selective 5»
`HTIBHD receptor agonist (a.k.a. triptans) that has been developed for the acute treatment of
`migraine with and without an aura. Extensive clinical experience and multiple clinical trials has
`demonstrated that oral zolmitriptan is typical of members of its class in its risk/benefit profile.
`
`The original application contained a single large (N=1547), double blind, placebo controlled,
`phase III efficacy trial (Trial 311CUS/077, hereafter trial 077) that clearly demonstrated efficacy
`for ZNS 5.0, 2.5, 1.0 and 0.5 mg using the clinical spray device. For the primary endpoint of
`headache response at 2 hours, all doses of zolmitriptan nasal spray were statistically superior to
`placebo (p<0.02 for ZN S 0.5 mg, all others <0.0001), with response rates of 68.9%, 55.3%,
`59.1%, and 39.6% for the 5.0 mg, 2.5 mg, 1.0 mg, and 0.5 mg doses, respectively, compared
`with 30.7% for placebol. Additionally 2 open label, long term safety trials were also conducted
`(Trail 31 1CIL/0078 and 3] lCIL/0122).
`
`The Approvable Letter cites a single deficiency with the original application, the lack of
`bioequivalence between the devices used in the majority of trial 077 and the devices intended for
`marketing. Several of the in-vitro bioequivalence parameters were outside the acceptable limits.
`The Approvable Letter outlines the following options on how the sponsor could remedy the
`deficiency.
`1. Repeat the in vitro testing using either mechanical actuation or have the break ring re-
`manufactured with more narrow specifications before repeating the study.
`2. Provide in vivo phannacokinetic data to demonstrate bioequivaience.
`3. Pravide efficacy data from a well designed, randomized controlled trial.
`In addition the sponsor was requested to submit revised draft labeling and a safety update.
`
`In a teleconference with the sponsor on February ll, 2003 we agreed that an interim analyses of
`the study 311CUS/0022 (hereafter trial 022) using the commercial device could possibly fulfill
`the deficiency relative to ZN S 5.0 mg. Trail 022 is an ongoing, large (N:1384), multicenter,
`randomized, placebo controlled study to evaluate the early efficacy (15 minutes) of ZNS 5.0 mg
`
`in the treatment of migraine. "
`———-—u———
`
`
`
`' Source: Sponsor Table 6, lSt AttackAnalysispdf, page 26 of original NDA submission.
`
`Page 4 of31
`
`

`

` CLINICAL REVIEW NDA 21-450
`
`Executive Summary Section
`
`As agreed this submission contains an interim efficacy analysis of trial 022, a safety update and
`revised draft labeling. For this review I use an abbreviated version of the suggested CDER
`template for NDA reviews. Specific details like PK/PD and chemistry summaries can be found
`in my original review and are not repeated here unless germane to the discussion. Primarily I will
`focus on the unblinded Interim Efficacy Analysis from trial 022 and the safety update report,
`most of which continues to be blinded. A review of the submitted revised labeling will be done
`in a separate document in order to facilitate team input.
`
`1. Recommendations
`
`1.] Recommendation 0n Approvability
`
`Considering the favorable risk-benefit balance seen with oral zoimitriptan use in migraine, and
`based on efficacy and safety data reviewed in this response to our Approvable Letter and the
`original NDA submission, and from a clinical perspective I recommend approval of Zomig
`(zolmitriptan) Nasal Spray 5.0 mg (NDA 21-450] for the treatment of acute migraine with and
`without an aura in adults.
`
`1.2 Recommendation on Phase 4 Studies and/or Risk Management Steps
`
`Phase IV commitments should include an evaluation of the bioequivalence between the clinical
`and proposed commercial device for ZNS ——-h 0.5 mg. Acceptable approaches include the
`same options outlined in the original Approvable Letter:
`1. Repeat the in vitro testing using either mechanical actuation or have the break ring re-
`manufactured with more narrow specifications before repeating the study.
`2. Provide in vivo pharmacokinetic data to demonstrate bioequivalence.
`3. Provide efiicacy data from a well designed, randomized controlled trial.
`
`Additionally as previously suggested in my original review the sponsor should continue with
`their development program to evaluate the safety and efficacy of ZNS in adolescent patients. The
`Sponsor has been granted a deferral for the pediatric migraine indication by agreement with the
`Agency.
`
`2. Summary of Clinical Findings
`
`2.1 Brief Overview of Clinical Program
`
`The efficacy database provided in this submission consist of an Interim Analysis of a single
`ongoing large efficacy trial (trial 022) using ZNS 5.0 mg in the prOposed commercial device.
`Trial 022 is a multicenter, randomized, double-blind, placebo controlled trial involving 1384
`patients to compare the efficacy and tolerability of ZNS 5.0 mg to placebo in the acute treatment
`of migraine using an early efficacy time point (15 minutes). The interim analysis was designed to
`evaluate the first 210 patients from 36 centers who treated the first migraine and provided
`efficacy assessments. The primary endpoint of the full study is to evaluate headache response at
`15 minutes. The primary endpoint of the Interim Analysis is to evaluate headache response at 2
`hours using first attack analysis...
`
`Page 5 of31
`
`

`

` CLINICAL REVIEW NDA 21-450
`
`Executive Summary Section
`
`The safety data base provided in this submission consists of 4 open label PK studies (SA-ZOE—
`0001, SA-ZOB-0002, 3‘11CIP/01 10, and 3] ICIL/0124) and two ongoing, double blinded,
`placebo-controlled efficacy and tolerability studies (Studies 31 1CUS/OO22 and 311CIL/0120). A
`brief description of each trial design can be found in section 2.1 of this review. Additionally the
`sponsor provides a brief discussion of post marketing safety reports from countries where ZNS
`5.0 mg is approved (Czechoslwakia, Iceland, Slovakia, Sweden, and the United Kingdom).
`
`Overall, new safety data is presented from 121 patients in the 4 pharmacokinetic studies (259
`exposures) and 1170 patients from blinded, placebo-controlled Studies 0022 and 0120 (2475
`exposures). Safety data from the placebo—controlled studies in this update remains blinded and
`unvalidated; therefore no distinction is made between patients who received 5.0 mg zolmitriptan
`nasal spray and patients who received placebo. In the clinical pharmacology studies 89 subjects
`were given ZNS 5.0 mg, 46 subjects received ZNS 2.5 mg, 21 subjects received ZNS 1.0 mg and
`12 subjects received zolmitriptan 10 mg. In trial 022 and 120 all subjects received ZNS 5.0 mg
`or placebo.
`
`2.2 Efficacy
`
`The Interim Analysis of trial 022 demonstrates statistical superiority of ZNS 5.0 mg, using the
`commercial device, for the primary endpoint of 2-hour headache response, when compared to
`placebo. The 2-hour headache response rate for the first treated migraine is demonstrated in the
`following sponsor table. As demonstrated in the table ZNS 5.0 mg using the commercial device
`was statistically better than placebo at relieving headache pain at two hours compared to placebo
`(p=0.0005).
`
`Table I Headache response at 2 hours (first attack) Interim analysis
`
`Population
`
`Zolmitriptnn S-mg nasal
`spray group
`[5:108]
`{erttzt
`
`
`Statistical comparison tlogisttc regression}
`
`Placebo group
`
`95% confidence
`Headache
`Number
`Headache
`Number
`assessed
`response
`assessed
`response
`interval (LU)
`
`ln ['l'bh'
`tn [‘lhj)‘
`
`Odds ratio
`
`p-Hillle
`
`ITT
`
`108
`
`76 (70.4]
`
`100’5
`
`47 (42.0)
`
`2.84
`
`I58. 5.l0
`
`0.0005
`
`’ Percentages are based upon the total number ofattaeks in the ITT for which data were atnilttble at 2 hours.
`95".1» Cl (LU) Lower and upper 95% confidence limits ol‘odds ratio ol‘headetrltc response rates for patients
`treated with zolmitriptan versus patients treated with placebo.
`b Two patients from the placebo group were not included in the analysis ofl-hour headache response: One
`patient had missing data at 2 hours: the other patient had taken escape medication before 2 hours when migraine
`headache pain was mild [these data were considered missing according to the SAP).
`ITT Intent to treat.
`Source: Sponsor table 13, interim nnalysls.pdl', page 45.
`
`The response rate for ZN S 5.0 mg using the commercial device (70.4%) is similar to the
`response rate for ZNS 5.0 mg using the clinical device in trial 077 (68.9%). However the
`treatment effect between trials is appreciably different. In this trial the treatment effect is 23.4%
`whereas in u-ial 077 the difference in response rates between ZNS 5.0 mg (clinical device) and
`placebo was 38.2%. Most of this difference is accounted for by a lower placebo response rate in
`trial 077 (30.7% vs. 47.0% in trial 022). The reason for the difference in response rates in
`subjects that received placebobetween the two trials is not apparent from my review.
`
`Page 6 of31
`
`
`
`
`
`tBESTPOSSIBLECOPY
`
`(”9‘
`
`
`
`

`

`
`
`CLINICAL REVIEW NDA 21-450
`
`Executive Summary Section
`
`The Interim Analysis of trial 022 does not demonstrate superiority for ZNS 5.0 compared to
`placebo in the percentage of subjects reporting resolution of their baseline nausea, photophobia
`or phonophobia (p20.0736). Despite this lack of superiority the response rate for ZNS 5.0 mg
`(clinical device) in trial 077 and ZNS 5.0 mg (commercial device) in trial 022 are nearly
`identical for each associated symptom. For some inexplicable reason the response rate for these
`endpoints in patients that received placebo in trial 022 were substantially larger than for the
`patients that-received placebo in trial 07?, resulting in a lower treatment effect. This as well as
`the small cohort size may explain the lack of significance for this secondary endpoint. The
`results did favor ZN S 5.0 mg numerically in trial 022 for each symptom.
`
`However the Agency analysis of the preportion of subjects reporting nausea, photophobia, or
`phonophobia demonstrates a clear advantage to ZNS 5.0 mg over placebo at 2 and 4 hours. As
`demonstrated in Table 8, ZN S 5.0 mg was statistically superior to placebo in the proportion of
`subjects reporting photophobia at 2 hours (p=0.0255). Likewise ZNS 5.0 mg was nearly
`significantly better than placebo for nausea at 2 hours (p=0.0796) and numerically better than
`placebo in the pr0portion of subjects reporting phonophobia (35.6% vs. 26.9%) at 2 hours.
`
`Although the analysis of associated symptoms results in mixed results it should be remembered
`this analysis only includes the first 210 subjects to complete the study. The efficacy of
`zolmitriptan against the associated symptoms of migraine has been demonstrated in other studies
`and is not the primary concern of this Interim Analysis.
`
`2.3 Safety
`
`The safety update report provides all new safety information between the period of the last
`update (June 27, 2002) up to the most recent cutoff date of December 31, 2002. Overall, new
`safety data is presented from 121 patients in 4 pharmacokinetic studies and l 170 patients from
`two blinded placebo controlled studies (trial 022 and trial 0120).
`
`In the four clinical pharmacology studies there were no deaths, serious adverse events, or
`withdrawal due to adverse events in any healthy volunteer. Across all nasal spray closes the most
`common adverse event was dysgeusia. The vast majority of adverse events were mild in intensity
`and of short duration.
`
`In the two controlled and blinded clinical trials (022 and 0120) the safety experience reported to
`date appears similar to the safety experience I previously reviewed for the full NDA. The
`sponsor uses the safety results from the cohort of subject receiving ZNS 5.0 mg (using the
`clinical device) in trial 077 as their primary comparison group for safety. A comparison of the
`blinded safety data from trial 022 and trial 0120 compared to trial 077 fails to demonstrate any
`new safety signals.
`
`In the two blinded placebo controlled trial using ZNS 5.0 mg (commercial device) there were no
`deaths and very few serious adverse events (3 to date, all unrelated to treatment). Withdrawal
`rates have been reasonable and comparable to withdrawal seen in trial 07? (approximately 1%).
`The common adverse events seen in trial 022 and 0120 appear to be similar in nature and
`
`Page7 of3l
`
`
`
`'_.-Ht-|‘
`
`

`

`
`
`CLINICAL REVIEW NDA 21-450
`
`Executive Summary Section
`
`incidence rates to the adverse events reported in trial 077. The most common adverse events was
`dysgeusia (unusual taste) in all studies (generally around 20%). Other common adverse events
`include dizziness, nasalpassage irritation, and throat imitation. The majority of reports were
`generally rated as mild to moderate and were of short duration. Subgroup analysis by age,
`gender, weight and race did not demonstrate any clinically significant differences between
`cohorts.
`
`Overall my review of the safety update report does not find any new safety concerns relative to
`the use of ZNS 5.0 mg using the commercial device. Since the majority of safety data provided
`in this safety update report is blinded or from open label uncontrolled PKJPD studies the new
`safety information is generally unacceptable for labeling purposes.
`
`24 Dosing
`
`The data providedm this submission supports the approval of ZN S 5.0 mg using the commercial
`device —————-————-——-——_.—._.'"_'-
`The closing regimen recommendations
`for ZNS 5.0 mg is unchanged from my original review, i. e., 1 Spray at the onset of a migraine
`with a repeated dose at 2 hours if required. The total amount of Zomig, in any formulation,
`should not exceed 10 mg in any 24 hour period.
`
`”PEAR THlS‘flfil
`
`Oil OiilGlliALY
`
`
`
`Page 8 of 31
`
`

`

`CLINICAL REVIEW 21-450
`
`Clinical Review
`
`1.
`
`Introduction and Background
`
`mg for the treatment
`The sponsor is developing Zomig Nasal Spray (ZNS) 5.0,
`of acute migraine. The original NDA was submitted on February 27, 2002. An Approvable
`Letter was issued December 19, 2002. This submission contains the complete response to our
`Approvable Letter. My original review and the Approvable Letter can be found in DFS. In this
`review I will strictly focus on the new material submittecLby the Sponsor on March 27, 2003.
`
`
`
`The original application contained a single large (N=1547), double blind, placebo controlled,
`phase III efficacy tn'al (Trial 311CUS/077, hereafter trial 077) that clearly demonstrated efficacy
`for ZNS 5.0, 2.5, 1.0 and 0.5 mg using the clinical spray device. For the primary endpoint of
`headache response at 2 hours, all doses of zolrnitriptan nasal spray were statistically superior to
`placebo (p<0.02 for ZNS 0.5 mg, all others <0.0001), with response rates of 68.9%, 55.3%,
`59.1%, and 39.6% for the 5.0 mg, 2.5 mg, 1.0 mg, and 0.5 mg doses, respectively, compared
`with 30.7% for placeboz. Additionally 2 open label, long term safety trials were also conducted
`(Trail 311CIL/0078 and 31 1C1L/0122). Additional details regarding the original NDA
`submission can be found in my original review in DFS.
`
`The Approvable Letter (dated 12/19/02) cites a single deficiency with the original application,
`the lack of bioequivalence between the clinical and proposed commercial spray devices. The
`letter outlines the following Options on how the sponsor could remedy the deficiency.
`1. Repeat the in vitro testing using either mechanical actuation or have the break ring re-
`manufactured with more narrow specifications before repeating the study.
`2. Provide in viva pharmacokinetic data to demonstrate bioeqaivalence.
`3. Provide eflicacy datafrom a we]! designed randomized controlled trial.
`In addition the sponsor was requested to submit revised draft labeling and a safety update.
`
`In a teleconference with the Sponsor on February 11, 2003 we agreed that an interim analyses of
`the study 311CUS/0022 (hereafter trial 022) using the commercial device could possibly fulfill
`the deficiency relative to the 5-Ing strength of Zomig Nasal Spray (ZNS). Trail 311CUS/0022 is
`an ongoing, large (N21384), multicenter, randomized, placebo controlled study to evaluate the
`
`early efficacy (15 minutes) of ZNS 5.0 mg in the treatment of migraine.
`t”
`
`This submission contains an interim efficacy analysis of trial 022, a safety update and revised
`draft labeling. Statistical superiority of ZNS 5.0 mg using the commercial device was found for
`the primary endpoint of 2-hour headache response when compared to placebo according to the
`prespecified Interim Analysis of trial 022. The safety update report provides all new safety
`information between the period of the last update (June 27, 2002) up to the cutoff date of
`December 31, 2002. Overall, new safety data is presented fiom 121 patients in 4
`
`2 Source: Sponsor Table 6, 1“ Attack-Analysispdf, page 26 of original NDA submission.
`
`Page 9 of3l
`
`

`

` CLINICAL REVIEW 21-450
`
`pharmacokinetic studies and 1170 patients from two blinded, placebo controlled, studies. The
`sponsor claims that the report indicates no new safety concerns for ZNS 5.0 mg although the
`safety database for the controlled trials are presented in a blinded manner. The sponsor states the
`new revised draft labeling includes all the changes suggested by the ‘Agency in our Approvablc
`Letter as well as the requested clarifications and editing changes. Additionally the sponsor has
`reformatted the Patient Information Leaflet into the suggested question/answer format using the
`current Relpax Patient Information Leaflet as a guide.
`
`For this review I use a truncated version of the suggested CDER template for NDA reviews.
`Specific details like PK/PD and chemistry summaries can be found in my original review and are
`not repeated here unless germane to the discussion. Primarily I will focus on the unblinded
`Interim Efficacy Analysis from trial 022 and the safety update report, most of which continues to
`be blinded. A review of the submitted revised labeling will be done in a separate document in
`order to facilitate team input.
`
`1.1 Important Milestones in Product Development (Updated)
`
`0 7 December 19, 2002
`0 February 11, 2003
`
`Approvable Letter sent to the sponsor
`Teleconference with sponsor to discuss deficiencies.
`
`II March 26, 2003
`
`Complete Response to Approvable Letter Received
`
`The Approvable Letter cites the lack of bioequivalence between the clinical and proposed
`commercial spray devices.
`
`In a teleconference with the sponsor on February 1], 2003 we agreed that an interim analyses of
`the study 311CUS/0022 (hereafter trial 022) using the commercial device could possibly fulfill
`the deficiency relative to the Surng strength of Zornig Nasal Spray (ZN S) only.
`
`2. Description of Clinical Data and Sources
`
`The efficacy database provided in this submission consist of an Interim Analysis of a single
`ongoing large efficacy trial (trial 022) using ZNS 5 .0 mg in the proposed commercial device.
`The safety data base provided in this submission consists of blinded safety data from trial 022
`and trial 120 plus 4 open label PK studies. Each of the studies are briefly described below.
`
`0
`
`0
`
`Clinical pharmacology studies:
`0
`SA-ZOB—OOOI: This was an open—label, 2-panel, non-randomized study in healthy volunteers
`to study the distribution of 5 .0 mg zolmitn'ptan nasal spray into the central nervous system in
`vivo using positron emission tomography.
`SA-ZOB~0002: This was an open-label, randomized, 4-way cross over, single—center study in
`healthy volunteers to determine the fraction intranasally absorbed of an intranasal dose of 5.0
`mg zolmitriptan.
`3IICIP/0110: This was a Phase I, double-blind, placebo-controlled, randomized, incomplete,
`crossover study in healthy volunteers to determine the safety, tolerability, and
`pharmacokinetics of 5.0 mg zolmitriptan nasal spray.
`31 lCIL/0124: This was a Phase I, open-label, randomized, single-dose, crossover study in
`healthy Japanese volunteerscto determine the safety and pharmacokjnetics of a 2.5 mg tablet
`
`-
`
`Page 10 of31
`
`

`

`CLINICAL REVIEW 21-450
`
`and 2.5 mg intranasal combined dose of zolmitriptan and a 5.0 mg tablet and 5.0 mg
`intranasal combined dose of zolmitriptan.
`
`Placebo-controlled, efficacy, safety, and tolerability studies (ongoing):
`0
`311CUS/0022: This is an ongoing multicenter, randomized, placebo—controlled, double-
`blind, parallel-group study to evaluate the early efficacy and tolerability of a 5.0 mg
`intranasal dose of zolmitriptan in the acute treatment of adult subjects with migraine.
`311CIL/0120: This is an ongoing multinational, multicenter, 2-phase study to assess the
`efficacy of and satisfaction with 5.0 mg intranasal zolmitriptan in the acute treatment of
`migraine when taken as required by the patient, by single attack comparison to placebo
`followed by an open-label treatment period with 5.0 mg intranasal zolmitriptan for 3 isolated
`attacks.
`
`-
`
`Only interim data from trial 022 will be reviewed for efficacy relative to ZNS 5.0 mg using the
`commercial device. All studies will be included in my safety discussion. The study reports for
`the 4 PK/PD studies are not included in this submission however the sponsor does include a
`summary of the safety findings from these studies in their Safety Report Update (SUR).
`
`3.
`
`Integrated Review of Efficacy
`
`In this section of my review I present the study design and efficacy results from the interim
`analysis of study 022 followed by my comments relative to this study only. Safety will be
`discussed in section 4. The first patient was enrolled on 10 September 2002. The study is
`presently ongoing.
`
`3.] Detailed Description of Trial 022
`
`Title: “A multicenter, Randomized, Placebo-controlled, Double-Blind, Parallel-Group Trial to
`Evaluate Early Efficacy and Tolerability of Zolmitriptan (Zomig) Nasal Spray in the
`Acute Treatment of Adults Patients with Migraine”
`
`Trial 022 is a multicenter, randomized, double-blind, parallel group, placebo controlled trial to
`compare the efficacy and tolerability of ZNS 5.0 mg to placebo in the acute treatment of
`migraine using an early efficacy time point (15 minutes). The trial is being conducted in 162
`centers in the United States. Evaluable patients can treat up to two migraines of moderate to
`severe intensity with study medication. Escape medication is prohibited for the first 4 hours after
`treatment. Following treatment subjects are instructed to return to the study site within 2 weeks
`of their last dose of study medication. The interim analysis was designed to evaluate the first 210
`patients from 36 centers who treated the first migraine and provided efficacy assessments. Only
`the Interim Analysis statistician and the SAS programmers had access to the unblinded treatment
`information for these 210 patients.
`
`The primary objective of the study is to evaluate the efficacy of ZNS 5.0 mg at 15 minutes in the
`acute treatment of migraine. The primary objective of the Interim Analysis is to evaluate efficacy
`at 2 hours of ZN S 5.0 mg compared to placebo in the acute treatment of migraine using first
`migraine attack data. Multiple attack analysis will be presented in the final report. Additionally
`efficacy relative to the associated symptoms will be assessed.
`
`Page 1] of3l
`
`K‘s.
`
`

`

`
`
`The full trial is expected to enroll approximately 1592 subjects meeting IHS criteria for migraine
`with and without aura to obtain 1384 evaluable patients (692 per cohort). It is estimated this
`sample size will provide 90% power to show a difference in headache response rate between
`ZNS 5.0 mg and placebo 15 minutes after treatment. Calculations were based on the assumption
`that the headache response rate at 15 minutes would be 6% for placebo and 11% for ZNS 5.0 mg.
`Although it is not relevant to the interim analysis, which uses a traditional 2-hour response rate, I
`am not inclined to believe a treatment effect of 5% at 15 minutes is clinically relevant.
`
`The inclusion and exclusion criteria for this trial are typical for most migraine trials. Included
`adult subjects are expected to have a migraine history of at least 1-year duration, be generally in
`good health and meet the IHS criteria for migraine with or without aura. Migraine frequency is
`not to exceed 6 migraine per month hence debilitated subjects with severe frequently recurring
`migraine were excluded.
`
`Restricted medications include the following:
`- MAOIs within 2 weeks of randomization.
`
`Unstable migraine prophylaxis within 2 months of randomization.
`
`Propranolol or cimetidine use.
`SSRI use within 2 months of randomization.
`
`Use of other migraine therapies (analgesics, anti-emetics, ergots, opiates, or other triptans)
`within 24 hours of use of study medication. Naratriptan is not to be used within 36 hours of
`treatment and Frovatriptan is not to be used within 5 days before trial treatment.
`
`The primary endpoint for the full study is headache response at 15 minutes after treatment.
`Headache response is defined as an improvement in headache pain from moderate to severe to
`none or mild using the 4-point scale typically seen in migraine studies. The sponsor should be
`encouraged to look at sustained early response as the primary endpoint.
`
`The primary endpoint f