`
`CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`APPLICATION NUMBER:
`202236Orig1s000
`
`
`STATISTICAL REVIEW(S)
`
`
`

`

`
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`
`
`U.S. Department of Health and Human Services
`Food and Drug Administration
`Center for Drug Evaluation and Research
`Office of Translational Sciences
` Office of Biostatistics
`
`
`
`
`
`
`
`
`Statistical Review and Evaluation
`CLINICAL STUDIES
`
`NDA/Serial Number:
`
`Drug Name:
`
`Indication(s):
`
`Applicant:
`Date(s):
`Review Priority:
`
`Biometrics Division:
`Statistical Reviewer:
`Concurring Reviewers:
`
`Medical Division:
`
`Clinical Team:
`
`NDA 202236/S0 (Cross references: IND 77363)
`Dymista (MP29-02) (azelastine HCl and fluticasone propionate
`Nasal Spray)
`Treatment of Seasonal Allergic Rhinitis (SAR) In Patients 12
`Years of Age and Older
`Meda Pharmaceuticals, Inc.
`Received 4/1/11; User Fee 2/1/12
`Standard
`
`Division of Biometrics II/Office of Biostatistics
`Feng Zhou, M.S.
`Joan Buenconsejo, Ph.D., Team Leader
`
`Division of Pulmonary, Allergy, and Rheumatology Products
`Jennifer Pippins, M.D. (Medical Reviewer)
`Susan Limb, M.D. (Medical Team Leader)
`Badrul Chowdhury, M.D., Ph.D. (Medical Division Director)
`Philantha Bowen
`Project Manager:
`
`
`
`
`Keywords: Clinical Studies, NDA review
`
`
`
`
`Reference ID: 3064362
`
`
`
`
`
`

`

`2.
`
`Table of Contents
`
`1. EXECUTIVE SUMMARY .................................................................................................... 4
`1.1
`Conclusions and Recommendations ............................................................................... 4
`1.2
`Brief Overview of Clinical Studies.................................................................................. 4
`1.3
`Statistical Issues and Findings........................................................................................ 5
`INTRODUCTION .................................................................................................................. 6
`2.1
`Overview ......................................................................................................................... 6
`2.1.1
`Class and Indication................................................................................................ 6
`2.1.2
`History of Drug Development ................................................................................ 7
`2.1.3
`Specific Studies Reviewed...................................................................................... 8
`2.2
`Data Sources................................................................................................................... 9
`3. STATISTICAL EVALUATION ............................................................................................ 9
`3.1
`Evaluation of Efficacy Studies ........................................................................................ 9
`3.1.1
`Study Design........................................................................................................... 9
`3.1.2
`Efficacy Endpoints and Assessment Schedule ..................................................... 10
`3.1.3
`Patient Disposition, Demographic and Baseline Characteristics.......................... 12
`3.1.4
`Statistical Methodologies...................................................................................... 13
`3.1.5
`Dose Selection ...................................................................................................... 15
`3.1.6
`Efficacy Results and Conclusions......................................................................... 15
`3.2
`Evaluation of Safety ...................................................................................................... 23
`4. FINDINGS IN SPECIFAL/SUBGROUP POPULATIONS ................................................ 24
`5. SUMMARY AND CONCLUSIONS ................................................................................... 25
`5.1
`Statistical Issues and Collective Evidence.................................................................... 25
`5.2
`Conclusions and Recommendations ............................................................................. 27
`6. LABELING........................................................................................................................... 28
`14.1. Seasonal Allergic Rhinitis................................................................................................ 28
`7. APPENDIX........................................................................................................................... 31
`SIGNATURES/DISTRIBUTION LIST ....................................................................................... 36
`
`
`
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`Reference ID: 3064362
`
`2
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`

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`LIST OF TABLES
`
`Table 1: Design of key controlled efficacy studies......................................................................... 9
`Table 2: Patients’ Accountability N (%)....................................................................................... 12
`Table 3: Patients’ Demographic and Baseline Characteristics N (%) .......................................... 12
`Table 4: Results of Change from Baseline in rTNSS over 2-weeks (Reviewer’s Analyses) ....... 16
`Table 5: Results of Change from Baseline in iTNSS over 2-weeks (Reviewer’s Analyses) ...... 18
`Table 6: The Analysis Results of Change from Baseline in rTOSS over 2-weeks....................... 20
`Table 7: Patients’ Who Were Excluded from the Applicant’s RQLQ Analysis N (%)................ 21
`Table 8: The Analysis Results of Change from Baseline in RQLQ over 2-weeks....................... 22
`Table 9: Patients’ Demographic and Baseline Characteristics N (%), Study MP4002 ................ 31
`Table 10: Patients’ Demographic and Baseline Characteristics N (%), Study MP4004 .............. 32
`Table 11: Patients’ Demographic and Baseline Characteristics N (%), Study MP4006 .............. 33
`Table 12: Summary of Pairwise Comparisons Resulting from Repeated Measures Analysis Using
`Imputed Scores or Raw Scores ..................................................................................................... 34
`
`
`LIST OF FIGURES
`
`Figure 1: Study Design ................................................................................................................. 10
`Figure 2: Treatment Comparison of LS Mean of Change from Baseline of rTNSS over 2-Week
`(Reviewer’s Analyses).................................................................................................................. 16
`Figure 3: Mean Score of rTNSS over 2-Week for Three Studies................................................. 17
`Figure 4: LS Mean of Individual Symptoms of rTNSS Score over 2-Week for three Studies..... 17
`Figure 5: Treatment Comparison of LS Mean of Change from Baseline of iTNSS over 2-Week18
`Figure 6: Treatment Comparison of LS Mean of Change from Baseline of iTNSS over 2-Week19
`Figure 7: Treatment Comparison of LS Mean of Change from Baseline of rTOSS over 2-Week20
`Figure 8: Treatment Comparison of LS Mean of Change from Baseline of RQLQ over 2-Week22
`Figure 9: Treatment Comparison of LS Mean of Change from Baseline of RQLQ over 2-Week23
`Figure 10: Responder Profile of Change from Baseline of RQLQ over 2-Week for Three Studies
`....................................................................................................................................................... 23
`Figure 11: LS Mean Change from Baseline of rTNSS over 2-weeks by Subgroup..................... 24
`Figure 12: LS Mean Change from Baseline of rTOSS over 2-weeks by Subgroup..................... 24
`
`
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`Reference ID: 3064362
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`3
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`

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`1.
`
`EXECUTIVE SUNIMARY
`
`1.1 Conclusions and Recommendations
`
`Meda Pharmaceuticals proposes Dymista® OVIP29-02) nasal spray for treatment of seasonal
`allergic rhinitis (SAR) in patients 12 years of age and older. Dymista consists of a fixed-dose
`combination of azelastine hydrochloride and fluticasone propionate, both approved medications
`in approved doses. Efficacy was assessed by a single primary endpoint, change from baseline in
`12-hour reflective Total Nasal Symptom Score (rTNSS) over the 14-day treatment period. «no
`
`The applicant claims that Dymista® is
`effective in decreasing in rTNSS compared to placebo and monotherapies
`(m4)
`and improving the quality-of-life compared to placebo in SAR patients aged 12 years and older.
`The applicant also clams that the onset of action was observed as early as 30 minutes following
`the initial dose of Dymista®.
`
`My statistical review of the clinical studies supports the claim of relief of the symptoms of
`seasonal allergic rhinitis in patients 12 years of age and older. In all three studies, there is
`evidence that Dymista is effective in decreasing rTNSS compared to placebo, as well as to each
`monotherapy. There is also evidence that Dymista is effective in improving the quality-of-life
`compared to placebo, and the observed effects met the minimum clinically significant diflerence
`of -0.50. The onset of action was observed at 30 minutes following the initial dose of Dymista.(m4)
`
`1.2 Brief Overview of Clinical Studies
`
`Dymista® (MP29-02) nasal spray consists of a fixed-dose combination of azelastine
`hydrochloride and fluticasone propionate. Each actuation of the MPZ9-02 nasal spray pump
`delivers 137 meg of azelastine hydrochloride and 50 mcg of fluticasone propionate such that l
`spray per nostril twice daily delivers a total daily dose of 548 mcg of azelastine hydrochloride
`and 200 mcg of fluticasone propionate.
`
`In this submission, the data supporting the efficacy of MP29-02 consisted of four phase 3 studies
`(MP4001, MP4002, MP4004, and MP4006) and one phase 3 safety study (lVIP4000). The design
`of Study MP4001 is different from other three phase 3 studies. Study MP4001 used Astelin®
`and fluticasone propionate nasal spray commercially available generic product as the
`comparator, not truly individual components of NIP29-02. Conclusion of efficacy of NIP29-2
`was mainly based on three efficacy studies (4002, 4004, and 4006).
`
`The studies MP4002, 4004, and 4006 are similar in design. The objective of these clinical trials
`was to compare the efficacy and safety of the combination of azelastine hydrochloride nasal
`spray and fluticasone propionate nasal spray (MPZ9—02) compared to placebo and to each
`
`Reference ID: 3064362
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`

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`component alone, in patients with symptomatic SAR. All treatments were administered at a
`dosage of 1 spray per nostril twice daily (total daily dose for MP29-02 was 548 mcg azelastine
`hydrochloride/ 200 mcg fluticasone propionate). The individual active controls (fluticasone
`propionate and azelastine hydrochloride) were formulated in the same delivery device as MP29-
`02. Efficacy was assessed by a single primary endpoint, change from baseline in 12-hour
`reflective Total Nasal Symptom Score (rTNSS) over the 14-day treatment period. Secondary
`endpoints included the change from Baseline in reflective and instantaneous Total Ocular
`Symptom Score (rTOSS and iTOSS, respectively); onset of action; the change from Baseline in
`the individual nasal symptom scores including nasal congestion and postnasal drip; and the
`change from Baseline in the Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ).
`
`
`
`1.3 Statistical Issues and Findings
`
`
`During my review of the clinical studies, I found no issues that could not be resolved by re-
`analyzing the data. The results generated by the applicant and by me are similar and do not
`change the overall conclusion.
`
`The major efficacy findings are as follows:
`
`
`• The treatment effect of MP29-02 nasal spray was measured by the change from baseline
`over the 14-day treatment period in combined AM+PM rTNSS. MP29-02 demonstrated
`statistically significant greater decrease in rTNSS than placebo and monotherapies except
`Study MP4004 (p=0.06). The treatment effects between MP29-02 and monotherapies and
`placebo ranged from 0.64 to 2.71 points with baseline score of 19 points (maximum of 24
`points). All protocol pre-specified sensitivity analyses supported the primary analysis
`results using repeated-measures analysis of covariance based on non-imputed data.
`Therefore, there is replicate evidence of the superiority of MP29-02 over placebo, as well
`as over each of the monocomponents (ie. azelastine and fluticasone propionate).
`
`• MP29-02 demonstrated statistically significant greater decrease in iTNSS compared to
`placebo and azelastine HCI only. The treatment effects between MP29-02 and azelastine
`HCI and placebo ranged from 0.70 to 2.63 points with baseline score of 18 points
`(maximum of 24 points).
`
`• MP29-02 demonstrated statistically significant greater decrease in rTOSS than placebo in
`all three studies and fluticasone propionate and azelastine HCI only in one study
`(MP4004). The treatment effects between MP29-02 and placebo ranged from 1.06 to
`1.56 points with baseline score of 12 points (maximum of 18 points). MP29-02 was
`numerically better than azelastine HCI in two studies. Although there is evidence that
`MP29-02 is superior to placebo in the ocular symptom endpoint (rTOSS), only one study
`showed factorial contributions of azelastine as well as fluticasone propionate to the
`combination, and this evidence was not replicated in the other two studies.
`
`5
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`Reference ID: 3064362
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`• Onset of action was a secondary endpoint for studies MP4002, MP4004, and MP4006.
`Beginning 45 minutes after the first dose, subjects who received MP29-02 in study
`MP4002 showed an improvement in iTNSS that was significantly better than the
`improvement seen by subjects who received placebo. For studies MP4004 and MP4006, a
`significant improvement over placebo was seen at 30 minutes in subjects who received
`MP29-02. For all studies, the significant improvement in MP29-02 over placebo was
`maintained at each time-point through the end of the 4-hour time course.
`
`•
`
`In all three studies, the treatment difference in the overall RQLQ score for MP29-02
`compared to placebo met the minimum clinically significant difference of -0.50 with
`baseline score of 4 points (maximum of 6 points). Therefore, there is evidence that
`MP29-02 is effective in improving the RQLQ score after 2-weeks of treatment in subjects
`aged 18 years and older with SAR.
`
`INTRODUCTION
`2.1 Overview
`
`
`
`
`
`
`2.
`
`
`2.1.1 Class and Indication
`
`Dymista® (MP29-02) nasal spray consists of a fixed-dose combination of azelastine
`hydrochloride and fluticasone propionate. Each actuation of the MP29-02 nasal spray pump
`delivers 137 mcg of azelastine hydrochloride and 50 mcg of fluticasone propionate such that 1
`spray per nostril twice daily delivers a total daily dose of 548 mcg of azelastine hydrochloride
`and 200 mcg of fluticasone propionate.
`
`Azelastine hydrochloride (Astelin® Nasal Spray; Meda Pharmaceuticals, Inc.), 137 mcg per
`spray, is a topical antihistamine, which was approved on November 1, 1996 in the United States
`(NDA 20-114) for treatment of seasonal allergic rhinitis (SAR) in patients 5 years of age and
`older and symptoms of non-allergic vasomotor rhinitis (VMR) in patients 12 years of age and
`older. The recommended dosage of azelastine hydrochloride in adults and children 12 years of
`age and older with seasonal allergic rhinitis is 1 or 2 sprays per nostril twice daily; for VMR, the
`dosage is 2 sprays per nostril twice daily (a total of 1096 mcg per day).
`
`Fluticasone propionate nasal spray (Flonase®; GlaxoSmithKline), 50mcg per spray, is a nasal
`steroid, which was approved on October 1994 in the United States (NDA 20-121) for treatment
`of seasonal and perennial allergic and non-allergic rhinitis in patients 4 years of age and older.
`Adult dosage is 200 mcg once-daily regimens (two 50-mcg sprays in each nostril once daily).
`
`The purpose of this submission is to obtain the approval of marketing in US of Dymista® nasal
`spray one spray per nostril twice daily for relief of the symptoms of seasonal allergic rhinitis in
`patients 12 years of age and older. The applicant claims that combining two agents with different
`mechanisms of action, ie, the antihistaminic action of intranasal azelastine hydrochloride (a
`selective histamine H1-receptor antagonist) and the anti-inflammatory effects of intranasal
`
`
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`Reference ID: 3064362
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`6
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`fluticasone propionate (a glucocorticosteroid), would have the potential for greater efficacy when
`used in combination than when used alone.
`
`2.1.2 History of Drug Development
`
`The clinical development plan for Dymista® nasal spray was introduced to the Division of
`Pulmonary, Allergy, and Rheumatology Products by Meda Pharmaceuticals, Inc. via IND 77363
`in April, 2007. Since then, the Division had several meetings and discussion with the applicant
`about their clinical program. On December 21, 2007, the applicant requested for a Special
`Clinical Protocol Assessment (Study MP4002). There was no statistical review was done and
`there was a no agreement reached. The Division provided the comments on January 17, 2008.
`The main points are as follows:
`
`0 As discussed in the June 25. 2007. teleconference and the September 10. 2007, meeting, we questioned
`the rationale of the proposed combination product, MP29-02 (azelastine hydrochloride/fluticasone
`propionate). According to 21 CFR 300.50, a combination product should be safe and effective for a
`significant patient population requiring such concurrent therapy. We do not believe that the proposed
`protocol MP4002 defines such a patient population, and you have not provided other evidence that
`such a significant population exists.
`
`0
`
`0
`
`The proposed fixed-combination product does not permit titration of the individual components as is
`possible with monotherapy treatment. This is especially concerning with intranasal corticosteroids,
`potentially exposing patients to excess corticosteroids and increased risk.
`
`The proposed efficacy study appears premature given the need for developing and characterizing
`appropriate monotherapy comparators to determine if a component interaction is present prior to a
`definitive Phase 3 study. Characterization should include in vitro performance comparison of the
`monotherapies compared to the combination product as well as pharmacokinetic comparisons.
`
`A type-A meeting was held on April 29, 2008, to discuss the Division’s SPA comments. The
`Pre-NDA meeting was held on August 17, 2010, the Division re-expressed its concerns about
`dose selection:
`
`0 A lower dose of MP29-02 is not required for NDA filing. However. we remain concerned about the lack of
`flexibility of dosage titration with the fixed dose combination. This lack of flexibility will be evaluated in
`the context of the available safety information. and will be a review issue.
`
`0
`
`-
`
`Ifthe systemic exposure from MP29—02 is equal or less than the systemic exposures for fluticasone and
`azelastine, respectively, from the corresponding commercially marketed monotherapies, then the proposed
`pharmacokinetic assessments will facilitate bridging to the systemic safety profiles established for the
`commercial monotherapies. Accordingly, a separate I-[PA axis effect trial with MP29-02 will not be
`required if you provide robust pharmacokinetic exposure data. However, the proposed pharmacokinetic
`data do not account for formulation differences that may alter the efficacy and local safety of locally acting
`products. Given this limitation, the results from MP4001 will likely be viewed as secondary support for the
`factorial contribution of azelastine and fluticasone to the efficacy of MPZ9-02.
`
`The Division finds the proposed indication for the treatment of nasal
`seasonal allergic rhinitis to be problematic.
`
`(h)(4) symptoms associated with
`a) (4)
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`Reference ID: 3064362
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`

`•
`
`Include in your NDA submission a rationale for the large sample size in MP-4006, which enrolled
`approximately double the patients enrolled in trials MP-4002 and MP-4004.
`• The protocol synopses for trials MP-4002, MP-4004, and MP-4006 do not state whether patients with a
`history of failed therapy with either Astelin or Flonase were excluded. Based on the information provided,
`we cannot ascertain whether an appropriate patient population requiring combination therapy was identified
`for these trials.
`
`
`Below is an excerpt of the discussion between the applicant and the Division.
`
`
`The Division recommended that Meda address the following issues in the NDA submission:
`1) Explain the rationale for an additional trial when typically two trials would be sufficient for establishing
`efficacy, and
`2) Explain the rationale for the large (doubled) sample size in trial MP-4006
`
`Meda agreed that they will provide explanation in the application. They added that the rationale for the
`additional trial and increased sample size was based upon previous trial results. Regarding the decision to
`conduct trial MP-4006, MP-4001 had yielded striking results, however, the results of MP-4002, while
`statistically significant, were not of the same magnitude as those for MP-4001, which prompted the company to
`conduct an additional trial. In addition, the total ocular symptom score (TOSS) had not been prespecified as an
`endpoint in trial MP-4002, which supported the decision to conduct an additional trial.
`
`The Division reminded Meda that in previous discussions there had been agreement on principles governing the
`issues of sample size, and asked for explanation of the large size of trial MP-4006. Meda responded that the
`results of trail MP-4002, which demonstrated a “delta” (effect size) that was smaller than anticipated, prompted
`the company’s decision to increase the sample size in order to be on the safe side.
`
`The Division stated that it will be important for Meda to make their case in their application, particularly given
`that there is no established minimum clinically important difference for seasonal allergic rhinitis. A product
`associated with a small treatment difference, but a significant p-value driven by a large sample size is
`undesirable. The Division recommended that Meda reflect back on the minutes of previous meetings during
`which this issue was discussed.
`
`Meda stated that the treatment difference associated with the combination product as compared to the
`monocomponents is comparable to that for non-sedating products compared to placebo. The Division responded
`that cross-study comparisons are fraught with difficulty. Meda replied that they will address the issue of clinical
`significance to the best of their ability in the NDA submission. Meda also asked whether there were any
`concerns regarding MP-4002 and MP-4004, to which the Division replied, no.
`
`
`2.1.3 Specific Studies Reviewed
`
`In this submission, the applicant submitted four phase 3 efficacy studies (MP4001, 4002, 4004,
`and 4006) and one phase 3 safety study (MP4000). The design of Study MP4001 is different
`from other three phase 3 studies. Study MP4001 used Astelin® and fluticasone propionate nasal
`spray commercially available generic product as the comparator, not truly individual components
`of MP29-02. Conclusion of efficacy of MP29-02 was mainly based on three efficacy studies
`(4002, 4004, and 4006). My review of efficacy will exclude the Study MP4001. Throughout the
`review, seasonal allergic rhinitis will be referred to as SAR, reflective total nasal symptom score
`as rTNSS, reflective total ocular symptom score as rTOSS, fluticasone propionate as FP,
`Azelastine hydrochloride as AH.
`
`
`
`
`Reference ID: 3064362
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`8
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`

`

`2.2 Data Sources
`
`All data was supplied by the applicant to the CDER electronic data room in SAS transport
`format. The data and final study report for the electronic submission were archived under the
`network path location \\...\cdsesub1evsprod\NDA202236.enx. The information needed for
`this review was contained in modules 1, 2.7, and 5.3.5.
`
`
` 3.
`
`
`STATISTICAL EVALUATION
`
`3.1 Evaluation of Efficacy Studies
`
`Study/Center
`/Study Period
`MP4001
`
`Phase 3
`8 sites during
`Texas Mountain
`Cedar allergy
`season
`12/20/2007 to
`2/19/2008
`MP4002
`
`Phase 3
`
`44 sites in US
`
`3/10/2008 to
`6/13/2008
`MP4004
`
`Phase 3
`
`41 sites in US
`
`8/14/2008 to
`11/3/2008
`MP4006
`
`Phase 3
`
`49 sites in US
`
`4/8/2009 to
`8/26/2009
`
`Primary
`Endpoint
`The overall
`change
`from
`Baseline at
`Day 14 in
`combined
`AM+PM
`rTNSS
`
`The overall
`change
`from
`Baseline at
`Day 14 in
`combined
`AM+PM
`rTNSS
`The overall
`change
`from
`Baseline at
`Day 14 in
`combined
`AM+PM
`rTNSS
`The overall
`change
`from
`Baseline at
`Day 14 in
`combined
`AM+PM
`rTNSS
`
`3.1.1 Study Design
`
`Table 1 presents the study design of these four studies which mainly collected efficacy and
`safety data to support MP29-02 in treatment of SAR in patients 12 years of age and older. The
`following review will only present the results from three studies (4002, 4004, and 4006).
`
`Table 1: Design of key controlled efficacy studies
`Key Inclusion
`# Patients by
`Study Design
`Criteria
`Group Entered
`1) MP29-02 nasal spray, 1 spray per
`Males and
`nostril BID: 153
`females, 12 years
`2) Astelin® nasal spray, 1 spray per
`and older, with at
`nostril BID: 152
`least a 2-year
`3) Fluticasone propionate nasal spray
`history of SAR
`(commercially available generic version),
`during Texas
`1 spray per nostril BID: 153
`mountain cedar
`4) Placebo nasal spray, 1 spray per
`season
`nostril BID: 151
`1) MP29-02 nasal spray, 1 spray per
`nostril BID: 207
`2) Azelastine hydrochloride nasal spraya,
`1 spray per nostril BID: 207
`3) Fluticasone propionate nasal sprayb, 1
`spray per nostril BID: 208
`4) Placebo nasal spray, 1 spray per
`nostril BID: 210
`1) MP29-02 nasal spray, 1 spray per
`nostril BID: 195
`2) Azelastine hydrochloride nasal spraya,
`1 spray per nostril BID: 194
`3) Fluticasone propionate nasal sprayb, 1
`spray per nostril BID: 189
`4) Placebo nasal spray, 1 spray per
`nostril BID: 200
`1) MP29-02 nasal spray, 1 spray per
`nostril BID: 451
`2) Azelastine hydrochloride nasal spraya,
`1 spray per nostril BID: 449
`3) Fluticasone propionate nasal sprayb, 1
`spray per nostril BID: 450
`4) Placebo nasal spray, 1 spray per
`nostril BID: 451
`
`
`Randomized
`Double-blind
`Placebo-controlled
`Parallel group
`Multi-center
`Active-controlled
`
`2-weeks treatment
`duration
`Males and
`Randomized
`females, 12 years
`Double-blind
`and older, with at
`Placebo-controlled
`least a 2-year
`Parallel group
`history of SAR
`Multi-center
`and a positive
`Active-controlled
`skin test to a
`2-weeks treatment
`local spring pollen
`duration
`Males and
`Randomized
`females, 12 years
`Double-blind
`and older, with at
`Placebo-controlled
`least a 2-year
`Parallel group
`history of SAR
`Multi-center
`and a positive
`Active-controlled
`skin test to a
`2-weeks treatment
`local fall pollen
`duration
`Males and
`Randomized
`females, 12 years
`Double-blind
`and older, with at
`Placebo-controlled
`least a 2-year
`Parallel group
`history of SAR
`Multi-center
`and a positive
`Active-controlled
`skin test to a
`
`local
`2-weeks treatment
`spring pollen
`duration
`a Formulated as MP29-02 without fluticasone propionate.
`b Formulated as MP29-02 without azelastine hydrochloride.
`
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`Reference ID: 3064362
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`9
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`

`The studies MP4002, 4004, and 4006 are similar in design. The objective of these clinical trials
`was to compare the efficacy and safety of the combination of azelastine hydrochloride nasal
`spray and fluticasone propionate nasal spray (MP29-02) compared to placebo and to each
`component alone, in patients with symptomatic SAR. All treatments were administered at a
`dosage of 1 spray per nostril twice daily (total daily dose for MP29-02 was 548 mcg azelastine
`hydrochloride/ 200 mcg fluticasone propionate). The individual active controls (fluticasone
`propionate and azelastine hydrochloride) were formulated in the same delivery device as MP29-
`02.
`
`Following a 7-day placebo run-in period, patients with allergy to prevailing individual seasonal
`pollen who met the minimum symptom severity requirement were randomized in a 1:1:1:1 ratio
`to receive MP29-02, azelastine hydrochloride, fluticasone propionate, or placebo. Patients were
`treated per protocol twice daily (AM and PM) for 14 days, during which they recorded nasal and
`ocular symptoms twice daily in a patient diary. The overall design of the study is depicted in
`Figure 1.
`
`The eligible patients include male and female patients 12 years of age and older with a minimum
`2-year history of SAR with a positive skin test to a local spring pollen during the previous year,
`who met all study inclusion/exclusion criteria, were eligible for randomization. All patients had
`moderate-to-severe symptomatic allergic rhinitis.
`
`
`Figure 1: Study Design
`
`
`
`3.1.2 Efficacy Endpoints and Assessment Schedule
`
`The primary endpoint is the change from baseline to day 14 in the 12-hour reflective TNSS
`(combined AM+PM rTNSS) for entire double-blind period. The AM+PM rTNSS score ranges
`from 0 to 24.
`
`Efficacy was assessed by patient ratings of symptom intensity as recorded in diaries for TNSS
`and TOSS, and by completion of the Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ)
`at specified intervals. Postnasal drip was scored at the same time, as a separate assessment.
`Patients were instructed to rate their nasal symptoms, ocular symptoms and postnasal drip, twice
`daily (AM and PM) in diaries prior to dosing.
`
`The following are secondary endpoints that were evaluated:
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`Reference ID: 3064362
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`1. Change from baseline in instantaneous TNSS (iTNSS) for the entire 14-day study period;
`2. Onset of Action (in Studies MP4002, 4004, and 4006 only)
`3. Change from baseline in 12-hours reflective individual symptom scores (including postnasal drip) for the
`entire 14-day stud period;
`4. Daily change from baseline in 12-hour reflective and instantaneous TNSS;
`5. Change from baseline in 12-hour reflective TOSS for the entire 14-day period;.
`6. Change from baseline in 12-hour reflective and instantaneous individual ocular symptom scores for the
`entire 14-day study period;
`7. Change from baseline to Day 14 in the RQLQ in patients 18 years of age and older;
`
`
`Information recorded in the TNSS section of the diary included:
`1. Runny Nose severity score
`2. Sneezing severity score
`3. Itchy Nose severity score
`4. Nasal Congestion severity score
`5. Time of dosing and number of sprays of study medications
`
`The severity scale for TNSS symptoms and postnasal trip is defined as:
`0 = None – no symptoms present
`1 = Mild – mild symptoms which are noticeable and do not interfere with any activity
`2 = Moderate – symptoms which are slightly bothersome and slightly interfere with activity OR nighttime sleep
`3 = Severe – symptoms which are bothersome and interfere with activity OR nighttime sleep
`
`Information recorded in the TOSS section of the diary included:
`1. Itchy eye severity score
`2. Watery eye severity score
`3. Eye redness severity score
`
`The severity scale for evaluation of Itchy Eyes and Watery Eyes is same as TNSS’s scale. The
`severity scale for Red eyes is defined as:
`0 = None – no redness present
`1 = Mild – slightly dilated blood vessels and pinkish color compared to patient’s normal color
`2 = Moderate – more dilation of blood vessels and red color compared to patient’s normal color
`3 = Severe – large, numerous dilated blood vessels and deep red color compared to patient’s normal color
`
`The RQLQ consisted of 7 domains which are rated on a 7-point scale with 0 being not troubled by the allergy
`symptoms during the past week, and 6 being extremely troubled (Table 1). The score of 9 was checked for
`Questions 1, 2 and 3, if the specified activity was not done. The total score for the questions within each domain was
`calculated. The RQLQ was only assessed at baseline and Day 14 in subjects aged 18 years and older. Domain score
`was calculated from the mean score of all items in the domain. Overall score was calculated from the mean score of
`all items and the maximum value is 6.
`
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`Table 1 Domain for RQLQ Questionnaire.
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`3.1.3 Patient Disposition, Demographic and Baseline Characteristics
`
`As shown in Table 2, a total of 3412 patients were enrolled at 134 centers in US; 3265 (96%)
`completed the 2 weeks of study. The reasons for discontinuation were similar among the 4
`studies. The pooled results for reason of early discontinuation were displayed in Table 2.
`
`
`Placebo
`210
`203 (97)
`210
`209
`198 (94)
`201
`190 (95)
`200
`200
`189 (94)
`451
`433 (96)
`451
`448
`413 (92)
`862
`826 (96)
`
`9
`0
`5
`4
`2
`2
`0
`8
`6
`36 (4)
`