AP&T Alimentary Pharmacology and Therapeutics
`
`Clinical trial: the incidence of NSAlD-associated endoscopic
`
`gastric ulcers in patients treated with PN 400 (naproxen plus
`
`esomeprazole magnesium) vs. enteric-coated naproxen alone
`
`J. L. Goldstein*, M. C. Hochbergl, J. G. Forti, Y. Zhangi, C. Hwang§ & M. Sostek§
`
`’Departme’i: oi Medicme. UniverSIty
`ot Illinois at Chicago. Chicago,
`IL,
`USA.
`
`lUniversi’y ot Maryland School ct
`Medicine, Baltinnorc, MD, USA.
`‘IPOZEN Inc, Chapel Hill. NC, USA.
`QAstraZe’Ieca. Wil'niagton, DE, USA.
`
`Correspondence to:
`Dr J. L GOICISlEI’I, Depa'tment of
`Medicine, University of Illinois at
`Chicago, 840 Sonia Wood Street
`(m/c787), Room '020 , 'ICti Floor.
`Chicago,
`IL 6062, USA.
`Email
`ilgoldst@uic.edu
`
`Publication data
`Sub’nitted 3'I March ZC'ID
`First decision 2‘ April 2CiO
`Resubmitted 70 May 20‘s")
`Acceated 20 May ZO’O
`Epuo Accepted Article 22 May ZOiC
`
`
`
`Background
`Gastroprolective co—Lherapy may reduce the risk of nonsleroidal anti-inflam-
`matory drug (NSAID)—associated gastric ulcers, but adherence is suboptimal.
`
`Aim
`
`To compare the incidence of gastric ulcers with PN 400 [enteric—coated
`(EC) naproxen 500 mg and immediate—release esomeprazole 20 mg], or EC
`naproxen.
`
`Methods
`
`Two randomized, double-blind, multicentre studies (PN400-301, PN400-
`302). Patients [stratified by 10 r-dose aspirin (S325 mg) use] aged 250 years
`or 18—49 years with a history of ulcer, received PN 400 BID (301, n = 218;
`302, n = 210) or EC naproxen 500 mg BID (301, n = 216; 302, n = 210)
`for 6 months. The primary endpoint was the cumulative incidence of endo-
`cv‘nnir nqotmr nlrnro
`scup... gastric mwvAu.
`
`Results
`
`The cumulative incidence of gastric ulcers was significantly lower with
`PN 400 vs. EC naproxen (301: 4.1% vs. 23.1%, P < 0.001; 302: 7.1% vs.
`24.3%, P < 0.001). PN 400 was associated with a lower combined incidence
`of gastric ulcers vs. EC naproxen in low—dose aspirin users (11 = 201) (3.0%
`vs. 28.4%, P < 0.001) and non—users (n = 653) (6.4% vs. 22.2%, P < 0.001).
`The incidence of, and discontinuations due to, upper gastrointestinal (UGI)
`AEs was significantly lower with PN 400 relative to EC naproxen (P < 0.01,
`both studies).
`
`Conclusions
`
`regardless
`PN 400 significantly reduces the incidence of gastric ulcers,
`of
`low—dose aspirin use,
`in at—risk patients, and is associated with
`improved UGI
`tolerability relative to EC naproxen (ClinicalTrials.gov,
`NCT00527782).
`
`© 2010 Blackwell Publishing Ltd
`doi:‘IO.TI‘Il/j.‘|365»2036.2010.04378.x
`
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`J. L. Goldstein et al.
`
`
`Chronic musculoskeletal diseases are highly prevalent
`and, with an ageing population,
`their
`incidence is
`increasingd’z Nonsteroidal
`anti-inflammatory
`drug
`(NSAID) therapy is one of the mainstays of treatment
`for the signs and symptoms of osteoarthritisf’7 but the
`impact of tolerability issues on long-term use is of con-
`siderable clinical concern in day-to-day practice. Chronic
`NSAID use is associated with a risk of upper gastrointes-
`tinal
`(UGI)
`injury and Loxicity,7’9 ranging from endo-
`scopic gastric ulcers in 15730% of NSAID users,10 to
`clinically relevant symptomatic ulcers and serious ulcer
`complications in 2—4% of users annually.9’ 11 \Nell-estab-
`lished risk factors for such complications include advanc-
`ing age, history of ulcers or UGI symptoms, high dose of
`NSAID and use of certain concomitant medications [cor-
`ticosteroids, anticoagulants and low-dose aspirin (LDA;
`75—325 mg)].12’ 13
`Co-prescribed proton pump inhibitors (PPIs) have
`been demonstrated to be an efficacious
`strategy for
`reducing the risk of NSAID-associated endoscopic ulcers
`in at-risk patientsM’m Based on these data coupled with
`additional evidence regarding ulcer complications, co-
`prescribed PPIs are one of the recommended treatment
`options in current preventive clinical guidelines.4’9’ 17
`However, despite these guidelines, gastroprotective co-
`therapies are often underprescribed or prescribed at in-
`adequate doses by physicians even in at-risk patientslg’23
`receive
`and, among those Who do
`gastroprotection,
`adherence is suboptimal, resulting in poorer clinical out-
`comesfl‘ 24‘ 25 Thus, beyond physician and patient edu-
`cation regarding the importance of adherence, there is a
`need for effective therapies to address the issue of
`NSAID-associated gastrointestinal (GI) toxicity in at-risk
`patients.
`Combining PPI delivery with an NSAID in a single-
`tablet formulation may circumvent the issue of poor clin-
`ical outcomes associated with non-adherence. PN 400
`
`(Patheon Pharmaceuticals Inc., Cincinnati, OH, USA on
`behalf of AstraZeneca, Wilmington, DE, USA and
`POZEN, Inc, Chapel Hill, NC, USA)
`is a fixed-dose
`combination formulation designed to provide sequential
`delivery of non-enteric-coated (EC),
`immediate-release
`(IR) esomeprazole 20 mg and EC naproxen (Patheon
`Pharmaceuticals Inc., Cincinnati, OH, USA) 500 mg in a
`single tablet.26’ 27 In these two phase 3 studies, treatment
`with PN 400 was compared with EC naproxen 500 mg
`alone over 6 months in at-risk patients to determine the
`incidence of cumulative endoscopic gastric ulcers and to
`evaluate safety and tolerability.
`
`402
`
`
`These two identical, 6—month, randomized, double-blind,
`
`parallel—group, controlled, multicentre, phase 3 studies
`(PN400—301 and PN400—302; NCT00527787) were con—
`ducted in 59 (study 301) and 70 (study 302) centres in
`the United States between September 2007 and Septem-
`ber 2008.
`
`if PN
`to determine
`The primary objective was
`400 reduces the risk of endoscopic gastric ulcers over the
`6-month duration of the studies in at—risk patients com—
`pared with EC naproxen alone. Secondary objectives
`were to determine if PN 400 reduces the risk of duode—
`
`nal ulcers, and to evaluate UGI symptoms and tolerabil-
`ity and safety profiles of PN 400 vs. EC naproxen. An
`additional objective was to evaluate the incidence of
`gastric ulcers in the subgroup of patients using LDA.
`These studies were reviewed and approved by an inde-
`pendent ethics committee (New England Institutional
`Review Board) or individual study site review board, and
`all patients gave written, informed consent in accordance
`with the 1996 Declaration of Helsinki. The studies are
`
`http://www.ClinicalTrialsgov
`
`(identifier:
`
`at
`registered
`NCT00527787).
`
`Patients
`
`included Helicobacter pylori-negative
`studies
`These
`patients (as determined by a stool antigen test) with cli-
`nician-diagnosed
`osteoarthritis,
`rheumatoid
`arthritis,
`ankylosing spondylitis or any other condition expected
`to require daily NSAID therapy for at
`least 6 months,
`who were either aged 250 years or aged 18—49 years with
`a documented history of uncomplicated gastric or duode-
`nal ulcer within the past 5 years.
`Patients with gastric or duodenal ulcer (23 mm diame-
`ter with depth) determined by endoscopy at baseline were
`excluded from these studies, as were patients with a his-
`tory of hypersensitivity or allergy to any PPI or NSAID,
`and/or with any uncontrolled acute or chronic medical
`illness. Other exclusion criteria included prior GI dis-
`orders or surgeiy, and history of alcohol or drug abuse.
`The use of any other NSAID (other than LDA), anticoag-
`ulants or bisphosphonates during the treatment phase was
`disallowed, as was use of any PPI, H2 receptor antagonist
`or sucralfate from within 2 weeks prior to baseline, and
`misoprostol from within 1 week prior to screening.
`At screening visit
`1, eligibility was established and
`patients provided informed consent. A physical examina-
`tion and an electrocardiogram were also performed.
`Following a washout period of up to 14 days, during
`which
`disallowed medications were
`discontinued,
`
`Aliment Pharmacol Tlier 2010; 32: 401—413
`© 2010 Blackwell Publishing Ltd
`
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`Clinical trial: PN 400 vs. EC naproxen — endoscopic gastric ulcers
`
`eligible patients returned for a second screening visit
`and baseline endoscopy. Patients with no evidence of
`ulcer at baseline were randomized.
`
`Study treatments
`Patients were stratified by LDA use (£325 mg) and ran-
`domized via the Interactive Voice Response System to
`receive either PN 400 or EC naproxen 500 mg alone,
`supplied as tablets of identical appearance in identical
`packaging to maintain blinding. The randomization sche-
`dule was provided by a third-party statistician. Patients,
`investigators and study staff remained blinded to treat-
`ment throughout the study.
`In the event of an emer-
`gency, an unblinding procedure was implemented.
`Both PM 400 and EC naproxen 500 mg were taken
`orally, twice daily, 30—60 min before a meal in the morn-
`ing and evening, for 6 months or until gastric ulcer was
`detected by endoscopy, at which point they were consid-
`ered to have completed the study. Study drug was dis-
`continued in the case of patient consent withdrawal,
`duodenal ulcer, pregnancy or any significant safety risk
`at the discretion of the investigator.
`Acetaminophen (as per
`label dosing guidelines for
`osteoarthritis) and liquid antacid (up to 6 x 5 mL/day)
`were supplied for supplemental pain management and
`relief of UGI discomfort.
`
`Study assessments
`The prospectively defined primary efficacy endpoint was
`the cumulative incidence of gastric ulcers (23 mm diam-
`eter with depth) observed by endoscopy at 1, 3 and
`6 months. To ensure an adequate sample size, a prespec-
`ified pooled analysis to assess the effect of LDA use
`(S325 mg) on gastric ulcer incidence in these NSAID
`users was also conducted.
`
`Prespecified secondary efficacy and tolerability end-
`points included the cumulative, observed incidence of
`endoscopic duodenal ulcers at 1, 3 and 6 months,
`the
`incidence of predefined NSAID-associated UGI adverse
`events (AEs)
`including duodenal ulcers throughout the
`study (Appendix), the proportion of patients discontinu-
`ing treatment as a result of NSAID-associated UGI ABS,
`and the proportion of patients discontinuing as a result
`of any AE. Due to their clinical
`importance, duodenal
`ulcers were considered to be a study endpoint and, as
`such, were not recorded as AEs, but were included in the
`
`analysis of NSAID-associated UGI AE and AEs leading
`to study discontinuation.
`The
`following patient-reported outcome question-
`naires were also conducted: Severity of Dyspepsia Assess-
`
`Aliment Pharmacol Ther 2010, 32; 401—413
`© 2010 Blackwell Publishing Ltd
`
`ment (SODA), Overall Treatment Evaluation—Dyspepsia
`(OTE—DP) and assessment of heartburn. The SODA
`questionnaire, completed at baseline and months 1, 3
`and 6, comprised 17 questions measuring three domains
`of dyspepsia: pain intensity, nonpain symptoms and sat—
`isfaction with dyspepsia—related healt11.28’29 Heartburn
`severity was also assessed at baseline and months 1, 3
`and 6. The OTE-DP questionnaire is a derivative of the
`Global Ratings of Change questionnaire30 and asked
`patients at month 6, ‘Since treatment started, has there
`been any change in your abdominal pain and/or discom—
`fort?’ Responses were rated as ‘better’, ‘worse’ or ‘same’,
`and those patients reporting a difference since treatment
`started were asked to describe the degree of change and
`importance of the change.
`treat-
`Safety was assessed by the incidence of ABS,
`ment-related ABS and serious AEs
`(SAEs), classified
`by the Medical Dictionary for Regulatory Activities
`(MedDRA) Version 10.1 and captured throughout
`the
`study via nondirective investigator questioning, patient
`reporting of symptoms, or
`through physical examina-
`tions,
`laboratory assessments and endoscopic findings.
`The following clinical
`laboratory tests were also per-
`formed: alanine transaminase, aspartate transaminase,
`alkaline phosphatase, bilirubin, blood urea nitrogen, cre-
`atinine and complete blood count at screening and/or
`baseline and at 1, 3 and 6 months.
`
`Statistical analysis
`The target sample size of 400 patients for each study, 200
`per treatment arm, was based on the assumption that
`15% of patients treated with naproxen would have a
`gastric ulcer over the 6-month study duration compared
`with 5% of patients treated with PN 400. A sample size of
`200 patients per treatment group in each study has 90%
`power to detect a treatment difference of 10% with a two-
`sided significance level of 5% using Fisher’s exact test.
`All efficacy analyses were performed on the intent-to-
`treat
`(ITT) populations (all
`randomized patients who
`received 21 dose of study drug and had no ulcer as
`detected by endoscopy at screening). Planned supportive
`analyses were performed on the per-protocol population
`(patients in the ITT population with no major protocol
`violation and treatment compliance 270%). Subgroup
`analyses included use of LDA (yes/no), age (<60 years or
`260 years) and history of ulcer within the past 5 years
`(yes/no).
`including cumulative frequency, was
`A summary,
`produced for the observed incidence of gastric ulcers
`at
`1, 3 and 6 months. The cumulative proportion of
`
`403
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`J. L. Goldstein et 0].
`
`patients developing gastric ulcers was analysed using a
`CochraneManteleIIaenszel
`(CMII)
`test
`stratified for
`LDA use. Time-to-event curves for the treatment groups
`were compared using a log-rank test stratified for [DA
`use. KaplaniMeier estimates and corresponding 95%
`confidence intervals (CIs) for gastric ulceration were cal-
`culated for each treatment group at 1, 3 and 6 months.
`In a post hoc analysis, relative risk reduction (RRR) for
`PN 400 responders was calculated (RRR 2 [event rate in
`the control group 7 event rate in the treatment group]/
`event rate in the control group),
`Treatment group comparisons were performed using a
`CMH test stratified by LDA use for the following key
`secondary endpoints in a hierarchical testing sequence to
`control the overall alpha rate at a 0.05 level: the propor-
`tion of patients with prespecified NSAID-associated UGI
`AEs; the proportion of patients discontinuing as a result
`of prespecified UGI AEs; and the proportion of patients
`developing duodenal ulcers during 6 months of treat-
`ment. The proportion of patients discontinuing the study
`due to any AE or duodenal ulcer was analysed using a
`CMH test stratified by LDA use.
`The mean change from baseline at 1, 3 and 6 months
`in the SODA scores was compared between treatment
`groups using an analysis of covariance model. The pro-
`portion of patients heartburn-free at 1, 3 and 6 months
`was analysed using a CMH test stratified by baseline
`heartburn severity and LDA use. The difference between
`treatment groups in distribution of responses on the
`OTE-DP was analysed using a modified Wilcoxon rank-
`sum test (Van Elteren).
`
`Safety analyses were based on the safety population
`(all randomized patients who received 21 dose of study
`drug). AEs were summarized for each treatment group
`and evaluated for severity and causality of study drug.
`Changes in clinical
`laboratory values from baseline to
`follow-up were summarized at each visit using descrip-
`tive statistics.
`
`
`
`Patients
`
`Of 635 patients screened in study 301, 438 patients were
`randomized, 434 were
`treated and 333
`completed
`(Figure 1a).
`In study 302, 639 patients were screened,
`423 were randomized, 420 were treated and 304 com-
`
`61 years in study 301 and 60 years in study 302. More
`than 80% of patients had osteoarthritis and approxi—
`mately 23% used LDA at randomization. Baseline demo-
`were
`graphics
`and
`characteristics
`similar
`between
`treatment groups in both studies, with the exception of
`the proportion of patients with rheumatoid arthritis,
`which was numerically higher in the PN 400 group com—
`pared with the EC naproxen group of study 301.
`
`Assessment of ulcer incidence
`
`In both studies, the cumulative observed incidence of gas—
`tric ulcers over 6 months was
`significantly lower
`in
`patients treated with EN 400 compared with those treated
`with EC naproxen (study 301: 4.1% vs. 23.1%, P < 0.001;
`study 302: 7.1% vs. 24.3%, P < 0.001). This translated to
`a RRR of 82.3% and 70.8% in studies 301 and 302,
`
`respectively. A significant difference was seen at month 1
`and maintained throughout the study (Figure 2).
`In a pooled analysis of both studies,
`the cumulative
`incidence of gastric ulcers was also significantly lower in
`the PN 400 group vs.
`the EC naproxen group in LDA
`users
`(11 = 201)
`and in LDA non-users
`(n = 653)
`(Figure 3).
`The cumulative incidence of duodenal ulcers was sig-
`nificantly lower in patients treated with PN 400 com-
`pared with those treated with EC naproxen (study 301:
`0.5% VS. 5.1%, P=0.003; study 302:
`1.0% vs. 5.7%,
`P = 0.007). This represented a RRR of 90.1% and 82.4%
`in studies 301 and 302. respectively.
`
`Tolerability
`In the ITT popu-
`Predefined NSAID-associated UGI AEs.
`lation,
`the incidence of predefined NSAID-associated
`UGI AEs was significantly lower in the PN 400 treat-
`ment groups compared with the EC naproxen groups in
`both studies (study 301: 52.3% vs. 69.0%, P<0.001;
`study 302: 54.3% vs. 71.9%, P < 0.001). The most com-
`mon UGI AEs occurring in 210% of patients in either
`the PN 400 0r EC naproxen treatment groups respec-
`tively of either study were erosive gastritis, gastritis,
`dyspepsia, and erosive duodenitis. A significantly lower
`proportion of patients discontinued due to UGI AEs
`(including duodenal ulcer) in the PN 400 groups com-
`pared with the EC naproxen groups (study 301: 3.2% vs.
`12.0%, P < 0.001; study 302: 4.8% VS. 11.9%, P = 0.009).
`
`pleted (Figure 1b).
`As
`seen in Table 1, approximately two-thirds of
`patients in the ITT populations of both studies were
`female. The mean age of patients was approximately
`
`Patient-reported outcomes. Patients treated with PN 400
`reported significantly better UGI
`tolerability compared
`with those treated with EC naproxen in terms of SODA
`scores, proportion of heartburn-free patients (Table 2),
`
`404
`
`Aliment Pharmacol Tlier 2010; 32: 401—413
`© 2010 Blackwell Publishing Ltd
`
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`Clinical trial: PN 400 vs. EC naproxen — endoscopic gastric ulcers
`
`(:3)
`
`
` _. Randvmizerl ,‘ ‘1“:
`
`(n = 433)
`
`PM 400
`n: 218
`
`I'I'I' population
`
`n = 21 B
`
`
`
`_. Premature dlscontlnuatlons
`(n = 67)
`- AE (n = 24)
`' Withdrew consent (n = 25)
`. Lost to follow-up (n = 2)
`. DU (n = 10)
`. Other (n = 6)
`
`
`
`Premature dlsconttnuatlons .—
`(11:35)
`-AE (n= 14)
`- Mthdrew consent (n = 13)
`- Lost to follow-up (n = 5)
`~DU (n: 1)
`- Other (n = 5)
`
`Completed study
`n = 180
`
`
`
`(b)
`
`Randomized
`(n = 423)
`
`
`n = 210
`
`PM 400
`n = 212
`
`HT population
`
`
`
`Premature disconfinuations <7
`(n=s1)
`'AE(”=2°)
`- Mthdrew consent (n = 24)
`- Lost to follow-up (n = 6)
`- DU (/1: 2)
`- Other (I! = 9)
`
`
`
`Premature discontinuations
`(n = 58)
`- AE (n = 30)
`- Withdrew consent (n = 8)
`- Lost to follow-up (n = 7)
`- DU (n = e)
`- Other (n = 5)
`
`Figure 1 | Patient disposition in
`(a) study 301 and (b) study
`302. lntent—to-treat (ITT) pop-
`ulation: received 21 dose of
`study drug and had no ulcer at
`screening. Completed study:
`patients who completed
`6 months of treatment or who
`discontinued due to gastric
`ulcer. EC, enterlc—coated; lTT,
`intent—to-treat; AE, adverse
`event; DU, duodenal ulcer.
`
`Completed study
`
`n = 1 51
`
`in both studies. In all
`and OTE-DP response (Table 3)
`three SODA domains (pain intensity, nonpain symp-
`toms and satisfaction), PN 400 was associated with sig-
`nificantly greater improvements from baseline compared
`with EC naproxen. Based on a comparison of the dis-
`tribution of primary OTE-DP responses (better, same
`or worse), PN 400 was associated with significantly
`greater improvement
`in upper abdominal pain and/or
`discomfort since treatment started relative to EC nap-
`roxen
`in
`study
`301
`(P < 0.001)
`and
`study
`302
`(P = 0.017).
`experienced
`those patients who
`Furthermore, of
`an improvement
`in upper
`abdominal pain and/or
`
`discomfort, a numerically greater proportion treated with
`PN 400 reported that the degree of change was at least
`moderately better or more compared with EC naproxen
`(study 301: 86.0% vs. 69.2%;
`study 302: 79.8% vs.
`61.9%). Conversely, of those patients who experienced a
`deterioration in symptoms, the proportion who reported
`the degree of change to be at least moderately worse or
`more was numerically similar or greater in the EC nap-
`roxen groups compared with the PN 400 groups (study
`301: 60.0% VS. 61.1%; study 302: 74.3% VS. 62.5%). It is
`noteworthy that, regardless of blinded treatment group,
`approximately 80% of patients in both studies consid-
`ered the change in OTE-DP to be important, specifically
`
`Aliment Pharmacol Ther 2010, 32; 401—413
`© 2010 Blackwell Publishing Ltd
`
`405
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`J. L. Goldstein et al.
`
`Table 1 | Patient demographics and baseline characteristics (ITT population)
`
`Study 301
`
`Study 302
`
`EC naproxen
`PN 400
`EC naproxen
`PM 400
`
`
`(n = 216)(n = 218) (n = 210)
`Gender, n (%)
`Female
`
`150 (68.8)
`
`149 (69.0)
`
`132 (62.9)
`
`142 (67.6)
`
`Age (years), mean (range)
`Race, 11 (%)
`White
`
`Black
`
`Other
`
`Weight (kg), mean (range)
`
`Height (cm), mean (range)
`
`BMl (kg/m2), mean (range)
`Smoker, n (%)
`LDA use at randomization, n (%)
`
`Indication for NSAID use, n (%)”
`
`Osteoarthritis
`Rheumatoid arthritis
`
`Other
`
`Ulcer history within previous
`5 years, n (%)
`
`60.8 (30—90)
`
`61.9 (43—90)
`
`59.6 (27—85)
`
`59.4 (29—82)
`
`184 (84.4)
`
`27 (12.4)
`
`7 (3.2)
`
`181 (83.8)
`
`32 (14.8)
`
`3 (1.4)
`
`88.1 (48.1—176.9)
`
`85.7 (51.5—166.0)
`
`183 (87.1)
`
`26 (12.4)
`
`190 (90.5)
`
`17 (8.1)
`
`1 (0.5)
`86.6 (503—1928)
`
`3 (1.4)
`87.1 (467—1574)
`
`166.6 (1473-1930)
`
`166.7 (147.3-205.7)
`
`167.1 (1499-1880)
`
`167.2 (1448-1956)
`
`31.7 (17.6—61.1)
`
`30.8 (20.1—56.5)
`
`30.9 (19.8—57.6)
`
`31.0 (19.0—55.2)
`
`32 (14.7)
`53 (24.3)
`
`172 (78.9)
`22 (10.1)
`
`53 (24.3)
`
`15 (6.9)
`
`27 (12.5)
`51 (23.6)
`
`186 (86.1)
`8 (3.7)
`
`38 (17.6)
`
`13 (6.0)
`
`36 (17.1)
`46 (21.9)
`
`173 (82.4)
`11 (5.2)
`
`48 (22.9)
`
`18 (8.6)
`
`38 (18.1)
`51 (24.3)
`
`166 (79.0)
`9 (4.3)
`
`59 (28.1)
`
`23 (11.0)
`
`iTT, intent-to»treat; EC, enteric—eoated; BMi, body mass index; LDA, low—dose aspirin; NSAID, nonsteroidal anti—inflammatory drug.
`* Patients may have had more than one indication for NSAID use.
`
`rated between moderately and extremely important
`(Table 3).
`
`Safety
`In the safety population, the overall incidence of treat-
`ment-emergent AEs was
`similar between treatment
`groups in both studies (study 301: 78.0% vs. 81.5%; study
`302: 76.2% vs. 82.9%)
`(Table 4). The most common
`treatment-emergent AEs were GI disorders
`(patient-
`reported and endoscopic findings), which were more
`frequent in the EC naproxen groups compared with the
`PN 400 groups (Tables 4 and 5).
`The incidence of ABS related to study drug was higher
`in the EC naproxen groups compared with PN 400
`groups in both studies (Table 4). Common treatment-
`related AEs included gastritis, erosive gastritis, dyspepsia
`and erosive duodenitis, reported by 210% of patients in
`either
`treatment group of either study.
`In study 301,
`SAEs
`related to study treatment were duodenal ulcer
`
`haemorrhage (n = 1) and noncardiac chest pain (11 = 1),
`both in the EC naproxen group. There were no treat-
`ment-related SAEs in study 302 or deaths in either study
`(Table 4).
`significantly lower proportion of
`a
`Additionally,
`patients treated with PN 400 discontinued from the
`study as a result of any AE (including duodenal ulcer)
`compared with those treated with EC naproxen in both
`studies (study 301: 6.9% vs. 15.7%, P = 0004; study 302:
`10.5% VS. 18.1%, P = 0.029).
`
`
`These two randomized, controlled, phase 3 studies were
`designed to assess the incidence of NSAID-associated
`endoscopic gastric ulcers following treatment with PN 400
`compared with EC naproxen alone in at-risk patients
`requiring chronic NSALD therapy. Our analyses consis—
`tently showed that
`the incidence of endoscopic gastric
`ulcers over 6 months of therapy was significantly lower
`
`406
`
`Aliment Pharmacol Ther 2010; 32: 401—413
`© 2010 Blackwell Publishing Ltd
`
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`Page 6 0f 13
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`Clinical trial: PN 400 vs. EC naproxen — endoscopic gastric ulcers
`
`(a) 40 —
`
`P < 0.001
`
`30 7
`
`|
`
`
`
`Patients(%) NO
`
`O _
`
`(b) 40 —
`
`30—
`
`|
`
`
`
`Patients(%) NO
`
`-a C)
`
`fi
`28
`
`3.0
`
`PN 400
`(n = 99)
`
`EC naproxen
`(n = 102)
`
`P < 0.001
`
` 10 7
`
`|
`
`PN 400
`(n = 329)
`
`EC naproxen
`(n = 324)
`
`0—
`
`Months
`
`Figure 2 I Cumulative observed incidence of gastric
`ulcers at months 1, 3 and 6 in (a) study 301 and (b)
`study 302 [intent—to-treat (lTT) population]. ITT,
`intent-to-treat; EC, enteric-coated.
`
`Figure 3 | Pooled cumulative observed incidence of
`gastric ulcers at month 6 in (a) low-dose aspirin (LDA)
`users and (b) LDA non—users [intent-to-treat (ITT)
`population]. LDA, low-dose aspirin; ITT, intent-to—treat;
`EC, enteric-coated.
`
`in patients treated with PN 400 compared with EC nap-
`roxen alone in both studies. Furthermore, a lower inci-
`dence of endoscopic duodenal ulcers was also noted in
`the active treatment arms.
`
`These studies measured the incidence of endoscopic
`gastric ulcers, a proposed biomarker (surrogate endpoint)
`for ulcer complications. The use of endoscopic ulcers is a
`subject of debate, with some arguing that this endpoint
`lacks clinical relevance and validity.31 However, endo-
`scopic ulcers can be considered relevant based on their
`
`Aliment Pharmacol Ther ZOlO, 32; 40i—4l3
`© 2010 Blackwell Publishing Ltd
`
`prognostic value for ulcer complications, and on evi-
`dence from many prospective and observational studies
`showing a trend for consistency of effect of interventions
`on both ulcer complications and endoscopic ulcers.32
`The PN 400 fixed-dose combination evaluated in the
`
`present studies provides sequential delivery of non-EC,
`IR esomeprazole 20 mg prior
`to release of EC nap—
`roxen.26’ 27 In a previous study comparing three dose
`combinations of PN 400 with naproxen 500 mg and EC
`
`407
`
`ATTORNEY CONFIDENTIAL
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`Page 7 0f 13
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`P2001 35224
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`Mylan v. Pozen
`lPR2017-01995
`
`I PN400(n=218)
`E EC naproxen (n = 216)
`
`P < 0.001
`
`P<0.001
`
`E
`
`L91
`
`P < 0.001
`
`4.1
`
`I6
`
`Months
`
`I PM 400 (n = 210)
`E EC naproxen (n = 210)
`
`P < 0.001
`
`a 30 —
`l)
`
`20 —
`
`10 7
`
`0 7
`
`3
`.9E
`
`gE
`
`(b) so —
`
`20—
`
`10—
`
`E.eE
`.2
`E
`
`
`
`
`
`
`
`
`
`
`Page 7 of 13
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`IPR2017-01995
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`

`

`J. L. Goldstein et al.
`
`
`
`Table 2 IUGI tolerablllty — change from baselineIn SODA scores and heartburn (ITT population)
`Study 301
`Study 302
`
`PN 400
`EC naproxen
`EC naproxen
`PN 400
`
`
`
`
`(n = 218) (n = 216) (n = 210) (n = 210)P value P value
`
`
`
`36BXLWEERZWEEQHQE'IFSEIESQeImew
`Pain intensity
`—5.51
`
`'
`
`Nonpain symptoms
`Satisfaction
`
`—2.16
`3.35
`
`Heartburn assessment
`
`—O.15
`
`—0.47
`0.87
`
`n:
`Heartburn—free at
`6 months n (%)
`
`177
`140 (79.1)
`
`115
`65 (56.5)
`
`<0.001
`<0.001
`
`<0.001
`
`—2.64
`—1.11
`
`1.88
`
`-
`
`141
`
`0.09
`0.11
`
`0.47
`
`121
`
`<0.001
`
`102 (72.3)
`
`62 (51.2)
`
`0.004
`<0.001
`
`0.003
`
`-
`
`<0.001
`
`UGI, upper gastrointestinal, SODA, Severity of Dyspepsia A;ssessment ITT, intent-to-treat; EC, enteric-coated, LSM, least squares
`means.
`
`* Last observation was carried fO'ward where scores were unavailable at month 6.
`
`I‘ A negative value for pain intensity and nonpain symptoms implies improvement, and a positive value for satisfaction implies
`improvement.
`1 Based on patients with heartburn assessment responses at both baseline and month 6.
`
`misoprostol (Arthrotec)4O and ibuprofen plus high-dose
`famotidine.41 These different approaches have been eval-
`uated in endoscopic studies comparing fixed-dose combi-
`nations with NSAIDs alone. As seen in our studies with
`
`PN 400,
`
`these combinations reduce the incidence of
`
`endoscopic gastric ulcers. Determination of relative effi-
`cacy across the different combinations would require
`direct head—to—head comparison.
`it was noted that the
`Of important clinical relevance,
`incidence of endoscopic gastric ulcers was reduced in
`LDA users
`significantly, and to a similar extent as
`observed in LDA non-users in both studies. Use of LDA
`
`for secondary prevention of
`increasingly prevalent
`is
`arterial thrombotic cardiovascular disease, but is known
`to increase the risk of NSAID-associated GI events.9
`
`However, our findings suggest similar efficacy, as mea-
`sured by endoscopic ulcer
`incidence, with PN 400
`regardless of LDA use. These findings are consistent with
`a previous subanalysis of concomitant LDA use from a
`study evaluating endoscopic gastric ulcer
`incidence in
`at-risk patients who were taking NSAIDs and lansopra-
`zole or misoprostolls’ 42
`The issues surrounding NSAID tolerability and their
`impact on long-term NSAID utilization that have been
`43745 are further validated here,
`reported in other studies
`of
`evidence
`trended together.
`where
`several
`lines
`Beyond the reduced incidence of UGI AEs observed in
`the PN 400 groups compared with EC naproxen,
`
`Aliment Pharmacol Ther 2010; 32: 401—413
`© 2010 Blackwell Publishing Ltd
`
`esomeprazole 20 mg administered separately in healthy
`volunteers, this non-EC, IR formulation of esomeprazole
`20 mg was demonstrated to provide comparable gastric
`acid suppression to EC esomeprazole 20 mg and did not
`affect the pharmacokinetics of naproxen.” 27
`In previously published studies, EC PPIs have been
`shown to resolve NSAID- asst) 21th symptoms of heart-
`3
`burn and acid regurgitation
`to prevent endoscopic
`14’ 15 and to
`ulcels in at-risk patients 1eceiving NSAIDs,
`reduce the incidence of recurrent ulcer complications34
`or bleeding in very high-risk patients.35737 Further obser-
`vational studies support
`the use of PMS to reduce the
`risk of ulcer complications
`in patients
`treated with
`NSAIDs.38’ 39 However, patient adherence to gastropro-
`tective cotherapy is suboptimal, leading to poorer clinical
`outcomes. For example,
`in two retrospective studies,
`adherence to gastroprotective agents among patients
`receiving NSAIDs was <40%.24’ 25 As a result, there is a
`need for greater physician and patient education, and
`strategies to improve patient compliance reliably and
`consistently, particularly among those receiving chronic
`NSAID therapy where adherence to co-prescribed gastro-
`protective agents decreases markedly over
`time.2“1’25
`Beyond education, the use of fixed-dose combinations of
`NSAIDs and gastroprotective agents is one strategy with
`potential to address the issue of adherence directly.
`Other attempts to provide NSAID therapy with gas-
`troprotection include combinations of diclofenac plus
`
`13
`
`408
`
`ATTORNEY CONFIDENTIAL
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`lPR2017-01995
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`

`

`Clinical trial: PN 400 vs. EC naproxen — endoscopic gastric ulcers
`
`Table 3 I OTE-DP — change in abdominal pain and/or discomfort since start of treatment (lTT population)
`
`Study 301
`PN 400
`(n = 204)
`
`EC naproxen
`(n = 187)
`
`Study 302
`
`PN 400
`(n = 184)
`
`EC naproxen
`(n = 183)
`
`samen(%)
`Better, n (%)
`
`.
`
`,, .
`
`93456)......
`93 (45.6)
`
`..................................95(508)89(484)85<464)
`52 (27.8)
`79 (42.9)
`63 (34.4)
`
`Almost the same, hardly better at all
`A little better
`
`Somewhat better
`
`Moderately better
`
`A good deal better
`
`A great deal better
`
`A very great deal better
`Worse, n (%)
`
`Almost the same, hardly worse at all
`A little worse
`
`Somewhat worse
`
`Moderately worse
`
`0 (0.0)
`5 (5.4)
`
`8 (8.6)
`
`15 (16.1)
`
`15 (16.1)
`
`25 (26.9)
`
`25 (26.9)
`18 (8.8)
`
`0 (0.0)
`4 (22.2)
`
`3 (16.7)
`
`6 (33.3)
`
`2 (3.8)
`
`8 (15.4)
`
`6 (11.5)
`
`5 (9.6)
`
`14 (26.9)
`
`8 (15.4)
`
`9 (17.3)
`
`40 (21.4)
`
`2 (5.0)
`6 (15.0)
`
`8 (20.0)
`
`1 (1.3)
`
`7 (8.9)
`
`8 (10.1)
`
`14 (17.7)
`
`15 (19.0)
`
`25 (31.6)
`
`9 (11.4)
`
`16 (8.7)
`
`O (0.0)
`3 (18.8)
`
`3 (18.8)
`
`2 (3.2)
`
`11 ( 7.5)
`
`11 ( 7.5)
`
`8 C 2.7)
`
`12 ( 9.0)
`
`12 ( 9.0)
`
`
`
`7 (1.1)
`
`35 ( 9.1)
`
`0 (0.0)
`4 ( 1.4)
`
`5 ( 4.3)
`
`A good deal worse
`
`A great deal worse
`
`A very great deal worse
`
`Importance of change (better/worse), r1 (%)
`
`Not important
`
`Slightly important
`Somewhat important
`
`Moderately important
`
`Important
`
`Very important
`
`Extremely important
`
`1 (5.6)
`
`3 (16.7)
`
`1 (5.6)
`
`(n = 111)
`
`6 (5.4)
`
`4 (3.6)
`8 (7.2)
`
`11 (99)
`
`24 (21.6)
`
`29 (26.1)
`
`29 (26.1)
`
`10 (25.0)
`8 (20.0)
`
`6 (15.0)
`
`0 (0.0)
`
`(n = 92)
`
`6 (6.5)
`
`6 (6.5)
`9 (9.8)
`
`15 (16.3)
`
`24 (26.1)
`
`21 (22.8)
`
`11 (12.0)
`
`4 (25.0)
`3 (18.8)
`
`3 (18.8)
`
`O (0.0)
`
`(n = 95)
`
`5 (5.3)
`
`2 (2.1)
`7 (7.4)
`
`11 (11.6)
`
`24 (25.3)
`
`3