CENTER FOR DRUG EVALUATION AND
`RESEARCH
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`APPLICATION NUMBER:
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`205103Orig1s000
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`STATISTICAL REVIEW(S)
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`REV-BIOMETRICS—OZ (Review Noted (NAI))
`NDA-205103
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`ORIG-l
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`Supporting Document 36
`Resubmission/Class 2
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`Form 3674
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`Submit Date: 06/30/2014 - FDA Received Date: 06/3 0/2014
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`This is a Complete Response (CR) resubmission of NDA 205103 for YOSPRALA
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`(aspirin/omeprazole) delayed release tablets, for use in the secondary prevention of
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`cardio- and cerebrovascular events in patients at risk of developing aspirin-associated
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`gastric ulcers, to the Complete Response (CR) letter dated April 25, 2014. The CR letter
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`identified two issues regarding facility inspections and labeling. This submission
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`contains the responses to the CR letter, revised product labeling and safety update
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`requested by the CR letter. Since this submission contains no new clinical efficacy data
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`for this formulation and the indication being pursued, a formal statistical evaluation is not
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`Reference ID: 3639632
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`This is a representation of an electronic record that was signed
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`electronically and this page is the manifestation of the electronic
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`signature.
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`FREDA COONER
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`10/06/2014
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`Reference ID: 3639632
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`Statistical Team Leader Memorandum
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`Submission: NDA 205103/000
`Product: Yosprala® (aspirin and omeprazole tablet)
`Sponsor: POZEN Inc.
`Indication: Secondary prevention of cardio- and cerebro-vascular events in patients at risk of
`developing aspirin-associated gastric ulcers.
`Medical Division: Division of Gastroenterology and Inborn Errors Products (DGIEP)
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`Reference: Statistical Review and Evaluation dated March 28, 2014.
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`The purpose of this memorandum is to summarize conclusions regarding the statistical issues
`discussed in the primary reviewer’s evaluation of the original NDA submission, and to present
`the Team Leader’s perspective on the study results.
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`The products for this application are PA8140 and PA32540 tablets (PA tablets) containing 81 mg
`and 325 mg delayed release aspirin, respectively, and 40 mg immediate release (IR) omeprazole.
`This is a 505(b)(2) submission to establish a bridge between the PA tablets (PA8140 and
`PA32540) and the reference listed drugs (RLD) Ecotrin® (325 mg and 81 mg), and to
`demonstrate the benefit of IR-omeprazole.
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`Two identically designed, adequate and well-controlled studies (PA32540-301 and PA32540-302)
`were concurrently conducted to investigate the efficacy of the PA32540 tablet. The sponsor is
`also seeking marketing approval of the PA8140 tablet, which has not been investigated in any
`phase 3 efficacy studies. Both PA8140 and PA32540 tablets are intended for use as a once a day
`(QD) therapy in the secondary prevention of cardiovascular and cerebrovascular events in
`patients at risk for developing aspirin-associated gastric ulcers.
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`The primary endpoint was the proportion of subjects developing gastric ulcers throughout six
`months of study treatment. The reviewer refers to this definition as “cumulative” rate and states
`in Section 3.1.1.4.1.1 that it is “the same as last-observation carried-forward (LOCF) analysis of
`this endpoint”. It should be clarified that the definition of the primary endpoint precludes
`implementation of the LOCF method for missing data imputation. For the primary analysis, only
`the subjects with endoscopic finding of gastric ulcer during the 6-month treatment period were
`counted as having gastric ulcer. As pre-specified, all other subjects were counted as gastric-ulcer
`free. These subjects included those who had six-month endoscopic results free of gastric ulcer or
`who discontinued before the study completion (either without endoscopic results or with
`endoscopic results showing no gastric ulcer). Conventionally, discontinued subjects are treated
`as “non-responders” or having gastric ulcers in this case. However, due to the fact that the
`comparator 325 mg EC-aspirin arm had more discontinuations than the treatment PA32540 arm
`in both studies, this conventional method would over-estimate the treatment effect. In other
`words, the pre-specified method of assuming discontinued subjects as gastric-ulcer free was
`conservative from our perspective.
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`The reviewer conducted exploratory analyses using “crude rate”, where “the subjects who were
`withdrawn prior to the study completion were assumed to be non-responders” (having gastric
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`Reference ID: 3479971
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`ulcer) as defined by the reviewer. Although the definition coincides with the conventional
`method mentioned above, the results presented in Sections 3.1.1.4.1.2 and 3.1.2.3.1.1 of the
`primary review did not match the reviewer’s definition. Instead, the results were the same as
`those from the primary analysis where discontinuations were counted as gastric-ulcer free.
`Moreover, the reviewer used the Fisher’s exact test when the assumptions underlying the FDA
`recommended Cochran–Mantel–Haenszel (CMH) test statistics are defensible, and the proper p-
`value for the primary comparison should be based on that pre-specified CMH analysis.
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`Extensive sensitivity analyses using different imputation methods on the missing data, including
`the worst-case analysis, were requested by the FDA and conducted by the sponsor. All the
`results showed favorable treatment effect for PA32540 comparing to EC-aspirin. The statistical
`significance stated in the primary review should be viewed with caution due to the exploratory
`nature of these sensitivity analyses. One should note that the aspirin-associated ulcer rate is
`generally low and with the relatively high discontinuation rates in both treatment arms, it is
`expected that some sensitivity analyses would generate p-values less than 5%. However, the
`results of these analyses, including the p-values, are exploratory only.
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`Some additional exploratory analyses results were also presented and/or discussed in the primary
`review. These analyses included the treatment comparisons on 1-month and 3-month gastric
`ulcer rates, and the reviewer’s Fisher’s exact test on the primary endpoint. The statistical
`significance of the results should also be viewed with caution due to their exploratory nature.
`Inferential statistics associated with these exploratory analyses are not suitable for the labeling.
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`In summary, the two phase 3 studies (PA32540-301 and PA32540-302) showed statistically
`significant benefit of the PA32540 tablet, compared to 325 mg EC-aspirin, as demonstrated by
`the primary efficacy endpoint and the four secondary and tolerability endpoints. These endpoints
`were pre-specified in the protocol and properly controlled for multiplicity.
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`Reference ID: 3479971
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`

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`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
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`/s/
`----------------------------------------------------
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`FREDA COONER
`03/28/2014
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`Reference ID: 3479971
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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
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`CLINICAL STUDIES
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`NDA#:
`Drug Name:
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`Indication:
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`Applicant:
`Date:
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`Review Priority:
`Biometrics Division:
`Statistical Reviewer:
`Concurring Reviewers:
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`205,103
`Yosprala PA8140 and PA32540 (aspirin/omeprazole) Tablet
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`Use in the secondary prevention of cardio- and cerebrovascular events in
`patients at risk of developing aspirin-associated gastric ulcers
`Pozen Inc.
`Receipt date: March 25, 2013;
`PDUFA goal date: January 24, 2014 (extended to April 25, 2014)
`Standard
`Division of Biometrics III
`Milton C. Fan, Ph.D., DB III
`Freda Cooner, Ph.D., Team Leader, DB III
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`Medical Division:
`Clinical Team:
`Project Manager:
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`Gastroenterology and Inborn Errors Products (DGIEP)
`Zana Marks, M.D., Robert Fiorentino, M.D. (TL) (DGIEP)
`Stacy Barley (DGIEP)
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`Keywords: clinical studies, NDA review, placebo-controlled
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`Reference ID: 3479643
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`1
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`Table of Contents
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`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
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`2.
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`2.1
`2.2
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`3.
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`INTRODUCTION …………………………………………………………………………5
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`OVERVIEW …………………………..…….……………………………………………………5
`DATA SOURCES………………………………………………………………............................6
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`STATISTICAL EVALUATION ……………………………………………………….7
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`3.1 EVALUATION OF EFFICACY ……………………………………………………….................7
`3.1.1 STUDY PA32540-301………………………………………………………………………… 7
`3.1.1.1 STUDY DESIGN …………………………………………………………………………….. 7
`3.1.1.2 PRE-SPECIFIED ANALYSIS ……………………………………………………………… 10
`3.1.1.3 APPLICANT’S ANALYSIS ………………………………………………………………….12
`3.1.1.3.1 PATIENT DISPOSITION……………………………………………………………………13
`3.1.1.3.2 ANALYSIS POPULATION ………………………………………………………………..13
`3.1.1.3.3 TREATMENT GROUP COMPARABILITY …………………………………………… 14
`3.1.1.3.4 APPLICANT’S ANALYSIS OF PRIMARY EFFICACY ENDPOINT….…………………14
`3.1.1.3.4.1 SENSITIVITY ANALYSES……………………………………………………………….16
`3.1.1.3.5 APPLICANT’S ANALYSIS OF SECONDARY EFFICACY ENDPOINT…………………17
`3.1.1.3.5.1 GASTRIC AND/OR DUODENAL ULCER …....................................................................17
`3.1.1.3.6 APPLICANT’S ANALYSES OF TOLERABILITY ENDPOINTS …………………………18
`3.1.1.3.6.1 TREATMENT SUCCESS ………………………………………………………………….18
`3.1.1.3.6.2 DISCONTINUATION DUE TO PRE-SPECIFIED UGI ADVERSE EVENTS …………. 19
`3.1.1.4. REVIEWER’S COMMENTS AND EVALUATION …………………………………………20
`3.1.1.4.1 ANALYSIS OF PRIMARY EFFICACY ENDPOINT …………………………………….. 20
`3.1.1.4.1.1 CUMULATIVE PROPORTION OF SUBJECTS DEVELOPING GASTRIC ULCER
` THROUGH 6 MONTHS ………………………………………………………..…………20
`3.1.1.4.1.2 CRUDE RATE AND MODIFIED CRUDE RATE………………………………….…… 21
`3.1.1.4.1.3 SUBGROUP ANALYSIES ……………………………………………….……………….21
`3.1.1.4.1.4 SENSITIVITY ANALYSES ……………………………………………………………….22
`3.1.2 STUDY PA32540-302………………………………………………………………………… 23
`3.1.2.1 STUDY DESIGN …………………………………………………………………………….. 23
`3.1.2.2 APPLICANT’S ANALYSIS ………………………………………………………………….. 23
`3.1.2.2.1 PATIENT DISPOSITION…………………………………………………………………. . 24
`3.1.2.2.2 ANALYSIS POPULATION …………………………………………………………………24
`3.1.2.2.3 TREATMENT GROUP COMPARABILITY ……………………………………………… 26
`3.1.2.2.4 APPLICANT’S ANALYSIS OF PRIMARY EFFICACY ENDPOINT… ………………… 26
`3.1.2.2.4.1 SENSITIVITY ANALYSES.
`28
`3.1.2.2.5 APPLICANT’S ANALYSIS OF SECONDARY EFFICACY ENDPOINT...……………… 29
`3.1.2.2.5.1 GASTRIC AND/OR DUODENAL ULCER ……………………………………………... 29
`3.1.2.2.6 APPLICANT’S ANALYSES OF TOLERABILITY ENDPOINTS ………………………...30
`3.1.2.2.6.1 TREATMENT SUCCESS ………………………………………………………………. 30
`3.1.2.2.6.2 DISCONTINUATION DUE TO PRE-SPECIFIED UGI ADVERSE EVENTS ……….
`30
`3.1.2.3. REVIEWER’S COMMENTS AND EVALUATION …………………………………………31
`3.1.2.3.1 ANALYSIS OF PRIMARY EFFICACY ENDPOINT …………………………………….. 31
`3.1.2.3.1.1 CRUDE RATE AND MODIFIED CRUDE RATE………………………………….…….. 31
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`2
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`Reference ID: 3479643
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`3.1.2.3.1.2 SUBGROUP ANALYSIES ……………………………………………….……………….32
`3.1.2.3.1.3 SENSITIVITY ANALYSES ……………………………………………………………….33
`3.2 EVALUATION OF SAFETY ………………………………………………………………………..34
`3.2.1 STUDY PA32540-301…………………………………………………………………………….34
`3.2.2 STUDY PA32540-302…………………………………………………………………………….34.
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`4.
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`FINDINGS IN SPECIAL/SUBGROUP POPULATIONS……………………… 36
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`4.1 GENDER, RACE, AND AGE …………………………………………………………………… 36
`4.1.1 STUDY PA32540-301 ………………………………………………………………………… 36
`4.1.2 STUDY PA32540-302 ... ….………………………………………………………………..…. 36
`4.2
`OTHER SPECIAL/SUBGROUP POPULATION ……………………………………………… 37
`4.2.1 STUDY PA32540-301 ……………………………………………………………………………37
`4.2.2 STUDY PA32540-302 ... ….……………………………………………………………………...37
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`5.
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`5.1
`5.2
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`SUMMARY AND CONCLUSIONS ………………………………………………… .38
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`STATISTICAL ISSUES AND COLLECTIVE EVIDENCE …………………………………… 38
`CONCLUSIONS AND RECOMMENDATIONS ……………………………………………… 38
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`6. APPENDIX ………………………………………………………………………………… 40
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`Table 1 Demographics and Other Baseline Characteristics - ITT Population Study PA32540-301……. 40
`Table 2Ulcer History and NSAID Use at Randomization – ITT Population Study PA325-301………… 41
`Table 3 Cardiovascular and Cerebrovascular Histories, co-Morbidities, and Clopidogrel Use at
` Randomization – - ITT Population Study PA32540-301...………………………………………42
`Table 4 Analysis of Cumulative Proportion of Subjects Developing Gastric Ulcers through 6 Months
` Modified - ITT Population Study PA32540-301…….…………………………………………. 43
`Table 5 Analysis of Cumulative Proportion of Subjects Developing Gastric Ulcers through 6 Months
` Per Protocol Population Study PA32540-301…….………………………………………….
`Table 6 Sensitivity Analysis – Observed Case Analysis – Study PA325-40-301………………….…..
`Table 7 Sensitivity Analysis –Worst-Case Analysis – ITT Population Study PA325-40-301…….…..
`Table 8 Analysis of Cumulative Proportion of Subjects Developing Gastric Ulcers of at least 5 mm in
` Diameter through 6 Months - ITT Population Study PA32540-301…….…………………
`Table 9 Analysis of Cumulative Proportion of Subjects Developing Gastric and/or Duodenal Ulcers of
` at least 5 mm in Diameter through 6 Months - ITT Population Study PA32540-301 ……….. 45
`Table 10 Demographics and Other Baseline Characteristics - ITT Population Study PA32540-302…… 46
`Table 11Ulcer History and NSAID Use at Randomization – ITT Population Study PA325-302.……… 47
`Table 12 Cardiovascular and Cerebrovascular Histories, co-Morbidities, and Clopidogrel Use at
` Randomization – - ITT Population Study PA32540-302. ..……………………………………48
`Table 13 Analysis of Cumulative Proportion of Subjects Developing Gastric Ulcers through 6 Months
` Modified - ITT Population Study PA32540-302…….…………………………………………. 49
`Table 14 Analysis of Cumulative Proportion of Subjects Developing Gastric Ulcers through 6 Months
`49
` Per Protocol Population Study PA32540-302…….………………………………………….
`Table 15 Sensitivity Analysis – Observed Case Analysis – Study PA325-40-302………………….….. 50
`Table 16 Sensitivity Analysis –Worst-Case Analysis – ITT Population Study PA325-40-302…….….. 50
`Table 17 Analysis of Cumulative Proportion of Subjects Developing Gastric Ulcers of at least 5 mm in
`51
` Diameter through 6 Months - ITT Population Study PA32540-302…….…………………
`Table 18 Analysis of Cumulative Proportion of Subjects Developing Gastric and/or Duodenal Ulcers of
` at least 5 mm in Diameter through 6 Months - ITT Population Study PA32540-302 ……… 51
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`Reference ID: 3479643
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`3
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`1.
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`EXECUTIVE SUNINIARY
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`1.1 Conclusions and Recommendations
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`Two studies, Studies PA32540-301 and PA32540-302, were conducted to evaluate PA32540 as
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`compared to enteric-coated GEO-aspirin 325 mg to support the proposed indication:
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`(It) (4)
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`In both Studies PA32540-301 and PA32540-302, the cumulative proportion of subjects
`developing gastric ulcers throughout six months was significantly lower with PA32540 vs. EC
`aspirin 325 mg. The treatment differences were 5% in Study PA32540-301 and 6% in Study
`PA32540-302.
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`1.2 Brief Overview of Clinical Studies
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`Studies PA32540—301 and PA32540 were identically design as a 6-month, phase 3, multi—center,
`randomized, double-blind, parallel-group, controlled trial to evaluate the incidence of gastric
`ulcers following administration of either PA32540 or EC aspirin 325 mg in subjects who are risk
`for developing aspirin-associated ulcer.
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`The primary objective of these studies was to demonstrate that PA32540 causes fewer gastric
`ulcers in subjects at risk for developing aspirin-associated gastric ulcers compared to EC aspirin
`325 mg.
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`The secondary objectives were:
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`0 To demonstrate that PA32540 causes fewer gastric and/or duodenal ulcers in subjects at
`risk for developing aspirin-associated ulcers compared to EC aspirin 325 mg;
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`0 To compare between treatments, the proportion of subjects with “Treatment Success”,
`defined as those subjects without gastric ulcers and without upper gastrointestinal
`(UGI)adverse events (AEs) leading to discontinuation;
`0 To compare between treatments, the proportion of subjects discontinuing the study due to
`UGI ABS;
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`0 To compare between treatments, the proportion of subjects with heartbrun resolution,
`defined as the answer “None” on the heartburn assessment question;
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`0 To evaluate the overall safety of PA32540 as compared to EC aspirin 325 mg.
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`Reference ID: 3479643
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`

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`Each study began with a screening period followed by a double-blind treatment period. After all
`entrance criteria were satisfied, subjects were randomized to either PA32540 or EC aspirin 325
`mg, taken orally, once daily.
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`1.3 Statistical Issues and Findings
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`Two studies, Studies PA32540-301 and PA32540-302, were conducted to evaluate PA32540 as
`compared to EC aspirin 325 mg to support the proposed indication.
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`In both studies, if an UGI ulcer was detected, the subject would be discontinued from the study.
`Interim endoscopies could be performed if clinically indicated. Ulcer was pre-specified as of size
`greater than or equal to 3 mm.
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`This reviewer performed analyses of the crude rate and the modified crude rate using the Fisher’s
`exact test. For the crude rate analysis, the subjects who were withdrawn prior to completion of
`the study were considered non—responders. This turns out to be the same as the primary analysis.
`For the modified crude rate analysis, the subjects who were withdrawn prior to completion of the
`study were excluded from the analysis. This turns out to be the same as the completed-case
`analysis.
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`Both analyses of developing gastric ulcer though six months using the Fisher’s exact test showed
`statistically significant lower rates with the PA32540 treatment than with EC aspirin 325 mg
`treatment.
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`Per this reviewer’s request, the applicant performed an analysis on the cumulative proportion of
`subjects developing gastric ulcers, duodenal ulcer, gastric and/or duodenal ulcers throughout six
`Month, where ulcer is defined as of size greater than or equal to 5 mm.
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`The results revealed a statistically significantly lower rate with PA32540 treatment than with EC
`aspirin 325 mg treatment for developing gastric ulcer, and gastric and/or duodenal ulcer.
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`2.
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`INTRODUCTION
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`2.1 Overview
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`PA8140 (aspirin 81mg/omeprazole 40 mg tables) and PA32540 (aspirin 325 mg/omeprazole 40
`mg tablets) was developed by the applicant as a delivery formulation of PA tablets allows
`omeprazole to be immediately release while the release of aspirin from the core is delayed
`dependent on the pH value. The applicant developed PA tablets to ensure that subjects who
`require chronic aspirin therapy will always receive a preceding omeprazole 40 mg.
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`The applicant is seeking marketing approval for PA8140 and PA32540 for the following
`indication.
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`(ll) (4)
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`Reference ID: 3479643
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`

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`(b) (4)
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`2.2 Data Sources
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`The applicant submitted Special Protocol Assessment (SPA) under IND 78,747 S/N 007 on J1me
`4, 2008. Statistical consultation was performed and documented. A non-agreement letters was
`issued on July 29, 2008.
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`The applicant also submitted Statistical Analysis Plan (SAP) for Studies PA32440-301 and
`PA32540-302 on September 1, 2011. Statistical Review and Evaluation was performed and
`documented on November 28, 2011. An advice letter was issued on November 29, 2011.
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`The comments to the applicant were:
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`0 We recommend your primary analysis use a CMH test stratified by the three NSAID use
`strata used for the randomization (Cox-2. other NSAID, or no NSAID users). Your proposed
`CMH test can be used as a supportive analysis.
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`0 Your primary analysis should be based on the ITT population defined as all randomized
`subjects. Your proposed ITT population is a modified ITT (mITT) population that can be
`used for a supportive or sensitivity analysis.
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`0 Expand your sensitivity analyses on the primaiy efficacy endpoint to investigate the impact
`of missing data on the efficacy conclusions. These could include completed-case. observed-
`case, worst-case, and multiple imputation methods.
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`The applicant has submitted two phase 3 studies (PA32540—301 and PA32540—302) for the
`proposed indication:
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`These two studies were entitled as follows:
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`0
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`0
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`Study PA32540-301: A 6-Month, Phase 3, Randomized, Double-Blinded, Parallel-Group,
`Controlled, Multi-Center Study to Evaluate the Incidence of Gastric Ulcers Following
`Administration of Either PA32540 or Enteric-Coated Aspirin 325 mg in Subjects Who
`Are at Risk for Developing Aspirin 325 mg .
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`Study PA32540-302: A 6-Month, Phase 3, Randomized, Double-Blinded, Parallel-Group,
`Controlled, Multi-Center Study to Evaluate the Incidence of Gastric Ulcers Following
`Administration of Either PA32540 or Enteric-Coated Aspirin 325 mg in Subjects Who
`Are at Risk for Developing Aspirin 325 mg
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`This original submission of this NDA was submitted in eCTD dated March 25, 2013.
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`Reference ID: 3479643
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`

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`The electronic submission can be viewed through
`\\cdsesub1\EVSPROD\NDA205103\205103.enx
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`The applicant submitted response on June 14, 2013, to this reviewer’s Information Request dated
`May 31, 2013.
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`The applicant submitted response on October 18, 2013, to this reviewer’s Information Requests
`dated October 4, 2013 and October 11, 2013.
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`3.
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`STATISTICAL EVALUATION
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`3.1 Evaluation of Efficacy
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`3.1.1 Study PA32540-301
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`3.1.1.1 Study Design
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`This study was a 6-month, phase 3, multi-center, randomized, double-blind, parallel-group,
`controlled trial to evaluate the incidence of gastric ulcers following the administration of either
`PA32540 or enteric coated (EC) aspirin 325 mg in subjects who are at risk for developing
`aspirin-associated ulcer.
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`The primary objective of this study is to demonstrate that PA32540 causes fewer gastric ulcers in
`subjects at risk for developing aspirin-associated gastric ulcers compared to EC aspirin 325 mg.
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`The secondary objectives were:
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` To demonstrate that PA32540 causes fewer gastric and/or duodenal ulcers in subjects at
`risk for developing aspirin-associated ulcers compared to EC aspirin 325 mg;
` To compare between treatments, the proportion of subjects with “Treatment Success”,
`defined as those subjects without gastric ulcers and without upper gastrointestinal (UGI)
`adverse events (AEs) leading to discontinuation;
` To compare between treatments, the proportion of subjects discontinuing the study due to
`UGI AEs;
` To compare between treatments, the proportion of subjects with heartburn resolution,
`defined as the answer “None” on the heartburn assessment question;
` To evaluate the overall safety of PA32540 as compared to EC aspirin 325 mg.
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`The study began with a screening period followed by a double-blind treatment period. After all
`entrance criteria were satisfied, subjects were randomized to either PA32540 or EC aspirin 325
`mg, taken orally, once daily.
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`Randomization was stratified based on chronic non-steroidal anti-inflammatory drugs (NSAIDs)
`use at baseline. Eligible subjects were stratified into three groups: 1) non-specific NSAID users;
`2) Cox-2 users; and, 3) subjects not currently on NSAIDs or Cox-2.Subjects taking NSAIDs
`were instructed to continue their prescribed NSAID therapy and report any changes to the
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`Reference ID: 3479643
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`7
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`

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`Investigator. Chronic NSAID use was defined as at least five days/week per prescribed dosage.
`Subjects were asked to report NSAID use monthly to site staff.
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`Subjects returned at one month (Visit 4) and three months (Visit 5) for safety assessments, an
`endoscopy and additional study drug. Also during each visit, subjects were asked about adverse
`events, NSAID use, and heartburn symptoms. If an UGI ulcer was detected, study drug would be
`discontinued, and the subject would be discontinued from the study and placed on appropriate
`medication, such as PPI, for treatment of the ulcer. Interim endoscopies could be performed if
`clinically indicated.
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`Subjects completing six months of therapy returned for a final visit at which final visit
`procedures, including an endoscopy would be performed.
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`The main criteria for inclusion were:
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`1. Male or non-pregnant, non-breastfeeding females who have been on daily aspirin 325 mg
`for at least three months and who are expected to use daily aspirin 325 mg for at least six
`months (daily is defined as “at least five days per week”):
`and, who are
`•
`55 years of age and older;
`or
`•
`
`18 - 54 years of age and have a history of a documented gastric or duodenal ulcer
`within the past five years.
`
`2. Aspirin use should be for the secondary prevention of cardiovascular or cerebrovascular
`events as defined as follows:
`Have been diagnosed with or have had a history of
`• MI (myocardial infarction that has been confirmed or suspected),
`•
`Ischemic stroke,
`• TIA (transient ischemic attack),
`or have established, clinically significant coronary and other atherosclerotic vascular
`disease (meaning at high risk for surgical intervention or for MI, TIA, stroke, if left
`untreated), including:
`• Angina (stable or unstable),
`•
`Peripheral arterial disease,
`• Atherosclerotic aortic disease,
`• Carotid artery disease,
`or have had
`• CABG (coronary artery bypass graft),
`•
`PCI (percutaneous coronary intervention with or without stent),
`• Carotid endarterectomy.
`
`The main criteria for exclusion were:
`
`1. Baseline endoscopy showing any gastric, esophageal or duodenal ulcer at least 3 mm in
`diameter with depth;
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`2. Positive test result for H. pylori at screening;
`3. Have had a revascularization procedure (i.e., CABG, PTCA or carotid endarterectomy)
`less than six months prior to screening;
`4. Unstable hypertension as judged by the Investigator;
`5. Uncontrolled diabetes mellitus as judged by the Investigator;
`6. Unstable cardio- or cerebrovascular disease such that it would endanger the subject if
`they participated in the trial;
`7. Clinically significant valvular disease;
`8. Congestive heart failure or other cardiovascular symptoms according to New York Heart
`Association (NYHA) Functional Classification III or IV;
`9. History of serious UGI event, such as bleeding, perforation, or obstruction;
`10. Gastrointestinal disorder or surgery leading to impaired drug absorption;
`11. Presence of chronic or uncontrolled acute medical illness, e.g. gastrointestinal disorder
`(esophageal stricture, severe esophagitis, long-segment Barrett’s esophagus, signs and
`symptoms of gastric outlet obstruction), thyroid disorder and/or infection that would
`endanger a subject if they were to participate in the study;
`12. History of alcoholism or drug addiction within a year prior to enrollment in the study
`13. Severe hepatic dysfunction (i.e., cirrhosis or portal hypertension);
`14. Blood coagulation disorder, including use of systemic anticoagulants such as warfarin or
`other vitamin K antagonists.
`
`Efficacy was assessed by gastroduodenal endoscopy at Screening (Visit 2), Visit 4 (Day 30),
`Visit 5 (Day 90 and Final Visit (Day 180) and by heartburn assessment at Baseline (Visit 3),
`Visit 4, Visit 5 and Final Visit.
`
`The actual assessment dates were used to define the “study day” on which assessments occurred
`relative to the randomization date. Visit windows for efficacy analyses were based on the actual
`study days outlined in the table below.
`
`Visit Windows
`
`The endoscopic assessment date was used to calculate the window for the subjects categorized as
`‘Gastric Ulcer’ or ‘Maintained Gastric Ulcer-Free’; the window for subjects categorized as
`‘Discontinued Gastric Ulcer-Free’ was calculated from the date of randomization to the date of
`withdrawal (the last date the subject was seen at the investigator site for study assessments).
`
`The gastroduodenal ulcer analysis followed the same data handling rules as those for the gastric
`ulcer analysis.
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`Study drug should be discontinued for a given subject if the Investigator determines that
`continuing might result in a significant safety risk for that subject. The following circumstances
`also required study drug discontinuation:
`
` Upper gastrointestinal ulceration
` Pregnancy
` A confirmed > 2.0g/dL decrease in hemoglobin
`
`Subjects, who discontinued study drug before completing the study, and those who prematurely
`withdraw from the study for any reason, should be scheduled for a visit as soon as possible, at
`which time all of the assessments listed for the final visit would be performed.
`
`A subject was considered to have completed the study if either one of the following criteria is
`met:
`
` Completion of six months of study drug treatment and the six month endoscopy
` Endoscopic confirmation of a gastric ulcer at any time during study drug treatment,
`including at the six month visit
`
`Note that subjects with duodenal or esophageal ulcers detected at any time during study drug
`treatment were not considered completers.
`
`3.1.1.2 Pre-specified Analysis
`
`The primary efficacy variable was the cumulative incidence of gastric ulcers at any time
`throughout six months of treatment.
`
`An ulcer was defined as a mucosal break of at least 3 mm in diameter (measured by e.g., close
`application of open endoscopic biopsy forceps) with depth. Endoscopies were performed at
`Screening Visit 2 prior to randomization and at one, three and six months during the treatment
`period. The applicant claimed effort was made to have the same endoscopist performing all
`endoscopies for a given subject.
`
`The secondary efficacy variable was the cumulative incidence of gastric and /or duodenal ulcers
`at any time throughout the six months of treatment. A duodenal ulcer was defined as a mucosal
`break of at least 3 mm in diameter with depth.
`
`The tolerability endpoints were:
`
`
`
`
` Proportion of subjects with “Treatment Success”, defined as those subjects without
`gastric
`ulcers and without UGI AEs leading to discontinuation;
`Incidence of subjects discontinuing the study due to UGI AEs at any time throughout six
`months of treatment;
`Incidence of subjects with heartburn resolution, defined as the answer “None” at the post-
`baseline heartburn symptom assessment. At baseline and one, three and six months all
`
`
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`subjects were asked the following question regarding heartburn symptoms within the
`seven days prior to the visit:
` Over the last seven days, please rate your heartburn symptoms as
`
`None: No symptoms;
`
`Mild: Awareness of symptom, but easily tolerated;
`
`Moderate: Discomforting symptom sufficient to cause interference with normal activities
`(including sleep);
`
`Severe: Incapacitating symptom, with inability to perform normal activities (including
`sleep);
`
`Heartburn definition - A burning feeling rising from the stomach or lower part of the
`chest towards the neck.
`
`The intent-to-treat (ITT) population consisted of all randomized subjects who received at least
`one dose of study drug and had no ulcer detected by endoscopy at screening. Subjects who had
`ulcers detected on the screen endoscopy or did not take any medication were excluded from the
`modified intent-to-treat (mITT) population. All efficacy analyses were performed using the ITT
`population. Following the ITT principle, subjects were analyzed according to the treatment they
`are assigned to at randomization.
`
`All subjects in the ITT population who did not violate the protocol in any major way that would
`impact the evaluation of efficacy constituted the per protocol (PP) population. Subjects who were
`excluded from the PP population were identified prior to the unblinding of the treatment code
`and the reason for exclusion was documented.
`
`The safety population consisted of all randomized subjects who receive at least one dose of study
`drug.
`
`For the baseline characteristics, qualitative data, such as, gender, race, age group, and history of
`gastric or duodenal ulcer will be presented in frequency tables. Quantitative data will be
`summarized by means of quantitative descriptive statistics (n, mean, median, standard deviation,
`minimum, and maximum).
`
`The primary analysis population was conducted on the Intent-to-Treat (ITT). The primary
`efficacy endpoint was analyzed using a Cochran-Mantel-Haenszel (CMH) test stratified by
`NSAID use [Yes (COX-2 or other)/ No] at randomization. No centers were pooled for analy