APgI Alimentary Pharmacology and Therapeutics
`
`Clinical trial: the incidence of NSAID-associated endoscopic
`gastric ulcers in patients treated with PN 400 (naproxen plus
`esomeprazole magnesium) vs. enteric-coated naproxen alone
`
`J. L. Goldstein*, M. C. Hochberg? J. G. Fort?, Y, Zhang", C. Hwang® & M. Sostek®
`
`*Departmen: of Medicine, University
`of Illincis at Chicago, Chicago,IL,
`USA,
`
`TUniversicy of Maryland Schocl ct
`Medicine, Baltirrore, MD, USA.
`4POZEN Inc, Chapel Hill, NC, USA.
`°AstraZereca. Wilmington, DE, USA,
`
`Correspondenceto:
`Dr. J.
`L. Goldstein, Department of
`Medicine, University of Illincis at
`Chicago, 840 Souta Wood Street
`(m/c787), Room “020 - 1Ctn Fleor,
`Chicage,
`IL 6C6°2, USA.
`E-mail:
`jlgoldst@uic.edu
`
`Publication data
`Subnitted 31 March 2C10
`First decision 2° April 2010
`Resubmitted ?0 May 2010
`Acceoted 20 May 20°0
`Epua Accepted Article 22 May 201C
`
`
`
`Background
`Gaslroproleclive co-therapy may reduce the risk of nonsteroidal anti-inflam-
`matory drug (NSAID) -associated gastric ulcers, but adherenceis suboptimal.
`
`Aim
`
`To compare the incidence of gastric ulcers with PN 400 [enteric-coated
`(EC) naproxen 500 mg and immediate-release esomeprazole 20 meg], or EC
`naproxen,
`
`Methods
`Two randomized, double-blind, multicentre studies (PN400-301, PN400-
`302). Patients [stratified by low-dose aspirin (<325 mg) use] aged 250 years
`or 18-49 years with a history ofulcer, received PN 400 BID (301, n = 218;
`302, n = 210) or EC naproxen 500 mg BID (301, » = 216; 302, n = 210)
`for 6 months. The primary endpoint was the cumulative incidence of endo-
`st
`ers,
`scopic gastric ulcers
`SCOPE pasulh
`
`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 (1 = 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 wassignificantly lower with PN 400 relative to EC naproxen (P < 0.01,
`both studies).
`
`Conclusions
`regardless
`PN 400 significantly reduces the incidence of gastric ulcers,
`af
`law-dose aspirin use,
`in at-risk patients,
`and=
`is associated with
`improved. UGI.
`tolerability relative to EC naproxen.
`(Clinicalrials.gov,
`NCT00527782).
`
`© 2010 Blackwell Publishing Ltd
`doi10.1111/j.1365-2036.2010.04378.x
`
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`J. L. Goldstein et al.
`
`
`
`
`
`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 al-risk patients com-
`pared with EC naproxen alone. Secondary objectives
`were to determine if PN 400 reduces the risk of duodc-
`
`nal ulcers, and to evaluate UGI symptomsand 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 paticnts using LDA.
`These studies were reviewed and approved by an inde-
`pendent cthics committee (New England Institutional
`Review Board) or individual study site review board, and
`all pationts gave written, informed consent in accordance
`with the 1996 Declaration of Helsinki. The studics are
`
`http://www.ClinicalTrials.gov
`
`(identifier:
`
`at
`registered
`NCT00527787).
`
`Patients
`
`Chronic musculoskeletal diseases are highly prevalent
`and, with an ageing population,
`their
`incidence is
`increasing.'~* Nonsteroidal
`anti-inflammatory
`drug
`(NSAID) therapy is one of the mainstays of treatment
`for the signs and symptoms of osteoarthritis,*” 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
`(UGT)
`injury and toxicily,’ ranging from endo-
`scopic gastric ulcers in 15-30% of NSATD users,2°
`to
`clinically relevant symptomatic ulcers and serious ulcer
`complications in 2-4% of users annually.'' Well-estab-
`lished risk factors for such complications include advanc-
`ing age, history of ulcers or UGT symptoms, high dose of
`NSAID and use of certain concomitant medications [cor-
`ticostcroids, anticoagulants and low-dose aspirin (LDA;
`75-325 mg)].’” 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 patients.‘*7° 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.*” ‘7
`included Helicobacter pylori-ncgative
`studics
`These
`However, despite these guidelines, gastroprotective co-
`patients (as determined by a stool antigentest) with cli-
`therapics are often underprescribed or prescribed at in-
`adequate doses by physicians even in at-risk patients'***
`nician-diagnosed
`osteoarthritis,
`rheumatoid
`arthritis,
`reccive
`ankylosing spondylitis or any other condition expected
`and, among those who do
`gastroprotcction,
`to require daily NSAID therapy for at
`least 6 months,
`adherence is suboptimal, resulting in poorer clinical out-
`comes.” ** ? Thus, beyond physician and patient edu-
`whowere either aged 250 years or aged 18-49 years with
`a documented history of uncomplicated gastric or duode-
`cation regarding the importance of adherence, there is a
`nal ulcer within the past 5 years.
`need for effective therapies to address the issue of
`Patients with gastric or duodenal ulcer (©3 mm diame-
`NSAID-associated gastrointestinal (GI) toxicity in at-risk
`ter with depth) determined by endoscopyat baseline were
`patients.
`Combining PPI delivery with an NSAID inasingle-
`excluded from these studies, as were patients with a his-
`tablet formulation may circumvent the issue of poor clin-
`tory of hypersensitivity or allergy to any PPI or NSAID,
`ical outcomes associated with non-adherence. PN 400
`and/or with any uncontrolled acute or chronic medical
`illness. Other exclusion criteria included prior GI dis-
`orders or surgery, 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, H» 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,
`
`(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.2> ?” 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 andtolerability.
`
`402
`
`Aliment Pharmacol Ther 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 visil
`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 Lo 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 PN 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.
`Acctaminophen (as per
`label dosing guidelines for
`osteoarthritis) and liquid antacid (up to 6 x 5 mL/day)
`were supplicd for supplemental pain management and
`relicf of UGI discomfort.
`
`Study assessments
`The prospectively defined primarycfficacy 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 samplesize, a prespec-
`ified pooled analysis to assess the effect of LDA use
`($325 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 AEs,
`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 health.” 7? 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 questionnaire*® and asked
`patients al 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 AEs,
`ment-related AEs and scrious AEs
`(SAEs), classified
`by the Medical Dictionary for Regulatory Activitics
`(McdDRA) Version 10.1 and captured throughout
`the
`study via nondircctive investigator questioning, paticnt
`reporting of symptoms, or
`through physical cxamina-
`tions,
`laboratory assessments and cndoscopic 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 cach 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%
`powerto detect a treatmentdifference 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 al.
`
`patients developing gastric ulcers was analysed using a
`Cochran—Mantel-Ilaenszel
`(CMII)
`test
`stratified for
`LDA use. Time-to-event curves for the treatment groups
`were compared using a log-rank test stratified for LDA
`use. Kaplan-Meier 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 = [event rate in
`the control group — 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 prespecificd 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 basclinc
`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-
`pleted (Tigure 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
`
`404
`
`61 years in sludy 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 PN 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 studics 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
`(n= 201)
`and in LDA non-users
`(m = 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 studics 301 and 302 respectively.
`
`Tolerability
`In the ITT popu-
`Predefined NSAID-associated UG! AEs.
`lation,
`the incidence of predefined NSAID-associated
`UGI AEs wassignificantly 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 or 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).
`
`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),
`
`Aliment Pharmacol Ther 2010; 32: 401-413
`© 2010 Blackwell Publishing Ltd
`
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`

`Clinical trial: PN 400 vs. EC naproxen - endoscopic gastric ulcers
`
`Screened
`(n= 635)
`
`Randomized —
`
`PN 400
`emi)
`
`ITT population
`
`(n= 498)
`n=218
`
`
`
`
`Premature discontinuations .__||_. Premature discontinuations
`(n= 38)
`(a= 67)
`* AE (n= 14)
`* AE (n= 24)
`+ Withdrew consent (n= 13)
`¢Withdrew consent (7 = 25)
`« Lost to follow-up (7 = 5)
`* Lost ta follow-up (a = 2)
`*DU (n= 1)
`* DU (n= 10)
`« Other (7 = 5)
`« Other (7 = 6)
`
`
`
`
`
`
`n= 210
`
`(a)
`
`(b)
`
`Figure: 1 | Patient disposition in
`(a) study 30] and (b). study
`302, Intent-to-treat: TT). pop-
`ulation: received 21 dose of
`study drug and had ne ulcer at
`screening. Completed study:
`patients who completed
`6 months of treatment or who
`discontinued due to gastric
`ulcer. EC, enteric-coated: ITT,
`intent-to-treat; AE, adverse
`event; DU, duodenal ulcer.
`
`
`
`
`Completed study
`n= 180
`
`— Screened |
`
`(oe 639)
`
`Randomized
`(n= 423)
`
`
`
`ee
`ar
`
`ITT population
`
`Premature discontinuations __|
`(n= 61)
`* AE (n= 20)
`¢ Withdrew consent (n= 24)
`* Lostto follow-up (7 = 6)
`* DU (n= 2)
`* Other (n= 9)
`
`Premature discontinuations
`(n= 58)
`© AE (n= 30)
`« Withdrew consent(n= 8)
`* Lostta follaw-up (1 = 7)
`* DU (n= 8)
`* Other (n = 5)
`
`Completed study
`
`n=151
`
`in both studies. In all
`and OTE-DP response (Table 3)
`three SODA domains (pain intensity, nonpain symp-
`toms andsatisfaction}, 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
`noteworthythat, 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
`
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`J. L. Goldstein et al.
`
`Table 1| Patient demographics and baseline characteristics (ITT population)
`
`Study 301
`
`Study 302
`
`EG naproxen
`PN 400
`EC naproxen
`PN: 460
`
`
`(n= 216)(i= 218) (4 = 210)
`Gender, n (%)
`Female
`
`150 (68.8)
`
`149 (69.0)
`
`132 (62.9)
`
`142:(67.6)
`
`Age (years), mean (range)
`Race, 1 (5)
`White
`
`Black
`
`Other
`
`Weight (ke), mean Crange)
`
`Height (cm), mean (range)
`
`BNI (ken); mean (range)
`Smoker, n (%)
`LDA usé at randomization, 4 (6)
`
`Indication for NSAID use, n (%)*
`
`Osteoarthritis
`Rheumatoid arthritis
`
`Other
`
`60.8 (30-90)
`
`619 (43-90)
`
`59.6 (27-85)
`
`59.4 (29-8?)
`
`184 (84.4)
`
`2/ (24)
`
`7 3.2)
`
`181 (83.8)
`
`32 (4.8)
`
`3 0.4)
`
`88.) (481-1769)
`
`85.7 (51.5-166.0)
`
`183 (8711)
`
`26 (24)
`
`190 (90.5)
`
`78.)
`
`1 (0.5)
`86.6 (50.3-192 8)
`
`3.0.4)
`87) (467-1574)
`
`166.6 (147.3-193.0)
`
`166.7 (147.3-205.7)
`
`167.1 (149.9-188.0)
`
`167.2 (144.8-195.6)
`
`3).7 U16-61.1)
`
`30.8 (20.|-56.5)
`
`30:9 (19.8-57.6)
`
`31.0: C19.0-552)
`
`32 (14.7)
`53 (24.3)
`
`172 (78.9)
`22 (10.1)
`
`53 24.3)
`
`27 (12.5)
`51 (23.6)
`
`186 (861)
`8 (3.7)
`
`38 (17.6)
`
`36 (17.1)
`AG (219)
`
`173 (82.4)
`TI (5.2)
`
`AS (22.9)
`
`38 (18.1)
`5] 24.3)
`
`166 (79.0)
`9 (4.3)
`
`59-(28.1)
`
`Ulcer history within previous
`5 years, n (%)
`(TT, intent-to-treat: EC, enteric-coated; BMI, body mass index: LDA, low-dose aspirin: NSAID, nonsteroidal anti-inflammatory drug.
`* Patients may have had more than oneindication for NSAID use.
`
`13 (6.0)
`
`18 (8.6)
`
`23 (11.0)
`
`15 (6.9)
`
`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 AEs 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 (» = 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 = 0.004; 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 NSAID 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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`

`

`Clinical trial: PN 400 vs. EC naproxen - endoscopic gastric ulcers
`
`P<0.001
`
`(a)
`
`
`
`Patients(%)
`
`40-—
`
`30 -
`
`20 -
`
`10 -
`
`PN 400
`(n= 99)
`
`EC naproxen
`(n= 102)
`
`(b) 40-—
`
`P<0,.001
`
`
`
`Patients(%)
`
`(n= 329)
`
`EC naproxen
`(n = 324)
`
`
`
`
` PN 400
`
`
`
`
`
`
`
`
`
`
`a) 30-
`°
`
`Hl PN 400 (n= 218)
`7 EC naproxen (n = 216)
`
`P<0.001
`
`P< 0.001
`
`23.1
`
`194
`
`P<0.001
`
`20
`
`105
`
`z
`2c
`
`s&
`
`41
`
`Z a
`0! =3
`Months
`
`6
`
`(b) 30-
`
`20 -
`
`=
`x=
`2ce
`2
`&
`
`| PN 400 (n = 210)
`[22 EC naproxen (n = 210)
`
`P<0.001
`
`P<0.001
`
`17.6
`eon
`
`P< 0.001
`
`Months
`
`Figure 2 | Cumulative observed incidence of. gastric
`ulcers at months 1, 3 and 6 in (a) study 3017 and (b)
`study 302 [intent-to-treat (TT) population]. (TT,
`intent-to-treat: EC, enteric-coated.
`
`Figure 3 | Pooled cumulative observed incidence of
`gastric ulcers at month © in €a)
`low-dose aspirin (LDA)
`users and Cb) 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.’
`Ilowever, endo-
`scopic ulcers can be considered relevant based on their
`
`Aliment Pharmacol Ther 2010, 32: 401-413
`© 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.*”
`The PN 400 fixed-dose combination evaluated in the
`
`present studies provides sequential delivery of non-ECC,
`IR esomeprazole 20 mg prior
`to release of EC nap-
`roxen.”* ?” In a previous study comparing three dose
`combinations of PN 400 with naproxen 500 mg and EC
`
`407
`
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`

`

`J. L. Goldstein et al.
`
`
`“Table2|UGItolerability ~ change from baseline in SODA scores and heartburn (ITT population)
`Study 301
`Study 302
`
`PN 400
`EC naproxen
`EC naproxen
`PN 400
`P value
`P-value
`Gr = 210)
`(n= 210)
`Cn = 218)
`(n= 216)
`SODA,LSMchangefrombaseline}
`Pain intensity
`5.5]
`
`<6.00)
`<0.001
`
`-2.64
`-111
`
`0.09
`on
`
`0.004
`<0.001
`
`<0,001
`
`1.88
`
`0.47
`
`0.003
`
`Nonpain symptoms
`Satisfaction
`
`—2.16
`3.35
`
`-0.47
`0.87
`
`Heartburn assessment
`
`-015
`
`nt
`Heartburn-free at
`6 months, n (%)
`UGI; upper gastrointestinal: SODA, Severity of Dyspepsia Assessment ITT, intent-to-treat; EC, enteric-coated, LSM, least squares
`Meas:
`
`.
`
`<0.001
`
`14]
`
`12]
`
`102 (72.3)
`
`62 (51.2)
`
`=
`
`<0.001
`
`177
`140 (791)
`
`5
`65 (56.5)
`
`* Last observation was carried fo-ward where scores were unavailable at month 6.
`
`+ A negative value for pain intensity and nonpain symptoms implies improvement, arid a positive value for satisfaction implies
`improvement.
`t Based on patients with heartburn assessment responses at both baseline and month 6.
`
`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.”® *”
`In previously published studics, EC PPIs have been
`Cla
`shown to resolve NSAID-associated symptoms of heart-
`33
`burn and acid regurgitation,
`to prevent endoscopic
`14, 15
`ulcers in at-risk patients receiving NSAIDs,
`and to
`reduce the incidence of recurrent ulcer complications*™
`or bleeding in very high-risk patients.*°*” Further obser-
`vational studies support
`the use of PPIs to reduce the
`risk of ulcer complications
`in patients
`treated with
`NSAIDs.*® *° 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%.*» * 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.** 7°
`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
`
`408
`
`misoprostol (Arthrotec)”® and ibuprofen plus high-dose
`famotidine.” These different approaches have been eval-
`uated in endoscopic studics comparing fixed-dosc combi-
`nations with NSAIDs alone. As seen in our studics with
`
`these combinations reduce the incidence of
`PN 400,
`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.”
`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 misoprostol.’* *
`The issues surrounding NSAID tolerability and their
`impact on long-term NSAID utilization that have been
`43-45 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
`
`ATTORNEY CONFIDENTIAL
`Page8 of 13
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`

`

`Clinical trial: PN 400 vs. EC naproxen - endoscopic gastric ulcers
`
`Table 3 | OTE-DP - change in abdominal pain and/or discomfort since start of treatment (ITT population)
`
`Study 301
`PN 400
`(i =204)
`samen(ou)icsannangsaseos
`Better, n (9%)
`93 (45.6)
`
`Study 302
`
`EC naproxen
`PN: 400
`EC naproxen
`(n= 183)
`(n= 184)
`(n= 187)
`soca5comgoabayaa
`52 (278)
`79 (42.9)
`63 (34.4)
`
`2 (3.2)
`
`175)
`
`11:75)
`
`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, (96)
`
`Almost the same, hardly worseatall
`A tittle worse
`
`Somewhat worse
`
`Moderately worse
`
`0 (0.0)
`5 (5.4)
`
`8 (8.6)
`
`45 (6A)
`
`15 (16.1)
`
`25 (26.9)
`
`25 (26.9)
`18 (S88)
`
`0 (0.0)
`4 (22.2)
`
`3 (16.7)
`
`6 (3.3)
`
`2 (3.8)
`
`815.4)
`
`6 (11.5)
`
`5 (9.6)
`
`14 (26.9)
`
`& (54)
`
`9 (17.3)
`
`40 14)
`
`2 (5.0)
`6 (15.0)
`
`8 (20.0)
`
`1 (1.3)
`
`TARO)
`
`& (10-)
`
`14027
`
`15 (19.0)
`
`25 (31.6)
`
`9 (11.4)
`
`16 (8.2)
`
`0 (0.0)
`3 (1.8)
`
`3 (18.8)
`
`4 (25.0)
`3 (18.8)
`
`
`
`8 27)
`
`12 (19.0)
`
`12 9.0)
`
`7 O11)
`
`35 91)
`
`0 (0.0)
`4 014)
`
`5 04.3)
`
`8 (229)
`1 GIA
`
`A good deal worse
`
`A great deal worse
`
`A very great deal worse
`
`Importance of change Cbetter/worse), 1 (%)
`
`Not important
`
`Slightly importaat
`Somewhat important
`
`Moderately important
`
`Important
`
`Very important
`
`Extremely important
`
`1 (5.6)
`
`3 (l6./)
`
`1 (5.6)
`
`(A= 11D
`
`6 (5.4)
`
`4 (3.6)
`8 (7.2)
`
`19.9)
`
`24 (21.6)
`
`29 (26)
`
`29 (2611)
`
`10 (25.0)
`8 (20.0)
`
`6 (15,0)
`
`0 (0.0)
`
`(n= 92)
`
`6 (6.5)
`
`6 (6.5)
`9 (9.8)
`
`15.6.3)
`
`24 (26.1)
`
`2) (22.8)
`
`Nl (12.0)
`
`318.8)
`
`0 (0.0)
`
`(n = 95)
`
`5 (5.3)
`
`2(2))
`7 7A)
`
`U.G1.6)
`
`24 (25,3)
`
`31 (32.6)
`
`15 (15.8)
`
`3 (8.6)
`
`4 (1A)
`
`(n = 98)
`
`5 (5.1)
`
`10 (10.2)
`1.2)
`
`10. (10.2)
`
`24 (24.5)
`
`22 (22.4)
`
`16 (16.3)
`
`in SODA scores
`
`and OTE-DP also
`
`improvements
`moved significantly in the same direction. Additionally,
`our
`study evaluated perception of UGI
`tolerability
`an