A single tablet multilayer formulation of

enteric-coated naproxen coupled with non-

enteric-coated omeprazole is associated
with a significantly reduced incidence of
gastric ulcers vs enteric-coated naproxen: a
prospective, randomized, double-blind study
Jay L. Goldstein,1 John G. Fort,2 Dennis S. Riff,3 Ying Zhang,2
Mark Sostek,4 John R. Plachetka2
1Department of Medicine, University of Illinois at Chicago,
Chicago, Illinois, USA; 2Pozen Inc., Chapel Hill, North Carolina,
USA; 3Advanced Clinical Research Institute, Anaheim,
California, USA; 4AstraZeneca, Wilmington, Delaware, USA
 AGA Disclosure
I have financial relationships with commercial
entities and the content of my presentation
includes discussion of off-label/investigative
use of medicine(s), medical devices,
or procedures.
AstraZeneca: consultant, honoraria, travel
expenses, research grants, speakers bureau
POZEN: consultant, honoraria, travel expenses,
research grants
Disclosure and Acknowledgements
z John G. Fort- POZEN: employee
z Mark Sostek- AstraZeneca: employee
z John R. Plachetka- POZEN: employee, patent
held/filed; Spouse- POZEN: Stock shareholder, board
membership

z Study PN200-301 was funded by POZEN Inc

z Editorial assistance was provided by Complete
Medical Communications, funded by AstraZeneca
 Introduction
z Efficacy of proton pump inhibitors
(PPIs) for the prevention of mucosal
injury, endoscopic ulcers, and upper
GI symptoms associated with NSAID
therapy is well documented1,2
z The degree of non-adherence to co-
prescribed medications reduces the
relative effectiveness of preventative
PPI therapy
1Hawkey et al. NEJM 1998; 2Scheiman Curr Treat Options Gastroenterol 2008
Non-adherence is associated with
decreased relative effectiveness
Annualized 0.4
rates of upper
GI events per
patient-year 0.3

R2 = 0.3088
0.2

0.1

0.0
0 20 40 60 80 100
Adherence (%)

Goldstein JL et al. Clin Gastroenterol Hepatol 2006

 Rationale for PN formulation
development

z Non-EC PPI component to optimize

PPI delivery prior to exposure to
NSAID
z A single tablet formulation of a
non-EC PPI and an EC NSAID could
address the issue of non-adherence
PN200: single tablet formulation

pH-sensitive Color film

film coat coat

Naproxen
core

Non-EC
omeprazole
 Study design (1)
z Randomized, double-blind, multicenter, parallel-
group, controlled study in patients requiring
chronic NSAID treatment*
stratified for ASA use 325 mg
z Inclusion criteria
Aged 18-49 with documented Hx of uncomplicated GU
or DU within the past 5 years, or aged 50 years (no Hx
required)
H. pylori-negative at screening
No antisecretory agents / misoprostol within 14 days
z Patients with baseline endoscopy showing any GU
or DU (3 mm diameter with depth) were excluded
*included patients with OA, RA, AS or other medical conditions expected to require
chronic NSAID treatment
 Study design (2)
Screening Baseline/ Safety Safety Safety
randomization evaluation evaluation evaluation
Consent Endoscopy Endoscopy Endoscopy Endoscopy

Begin study
medication
PN200 BID

Washout
for PPIs
End of study

EC naproxen 500 mg BID

Day -14 to -7 Day 1 Day 30 Day 90 Day 180

 Study endpoints

z Primary endpoint
Survival analysis of incidence of GU
(>3 mm diameter with depth) over 6
months
z Secondary endpoints
Incidence of DU over 6 months
Tolerability
Safety
 Study disposition
Screened (n=649)

Randomized (n=413)

PN200 EC naproxen
(n=207) (n=206)

ITT population ITT population

(n=206) (n=203)
Prem. discontinuations (n=51) Prem. Discontinuations (n=68)
AE (n=24) AE (n=30)
Withdrew consent (n=14) Withdrew consent (n=9)
Lost to follow-up (n=3) Lost to follow-up (n=3)
Duodenal ulcer (n=1) Duodenal ulcer (n=14)
Other (n=9) Other (n=12)

Completed study Completed study

(n=155) (n=135)

ITT (intent-to-treat) population: all patients randomized who received at least one dose of study
drug with no ulcer at baseline
(At baseline: 4 subjects: 1 PN200, 3 EC naproxen)
 Demographics ITT
PN200 EC naproxen
(n=206) (n=203)
Gender, n (%) Male 73 (35) 60 (30)

Race, n (%) White 175 (85) 173 (85)

Black 24 (12) 20 (10)
Other 7 (3) 10 (5)

Age (years) Mean 60.8 60.7

<60 years, n (%) 106 (51) 100 (49)
50 years , n (%) 199 (97) 201 (99)

Aspirin use, n (%) 56 (27.2) 52 (25.6)

Ulcer Hx, n (%) Gastric only 13 (6.3) 4 (2)

Duodenal only 2 (1) 0
 Primary endpoint: survival analysis
of incidence of gastric ulcers ITT
**
72% RR
40
Gastric ulcers, cumulative %

PN200 (n=206)
35 29.4%
EC naproxen (n=203) (22.9-37.3)
30
23.1%
25 (17.4-30.3)

20
15 10.3%
(6.9-15.4) 8.3%
10 5.1% (5.1-13.5)
3.4% (2.8-9.3)
5 (1.6-7.0)

0
1 month 3 months 6 months
**p<0.001 between groups over 6 months
Data shown are % (CI)
 Cumulative observed incidence of
gastric ulcers ITT

35 **
PN200 (n=206) **
30
Gastric ulcers, %

EC naproxen (n=203) 23.6%

25 (18.0-30.1)
19.7%
(14.5-25.9)
20 *

15 10.3%
(6.5-15.4) 7.3%
10 4.9% (4.1-11.7)
3.4%
(2.4-8.7)
5 (1.4-6.9)
7/206 21/203 10/206 40/203 15/206 48/203
0
1 month 3 months 6 months
*p<0.01; **p<0.001
Data shown are % (CI)
Cumulative incidence of gastric ulcers at
6 months: ASA vs no ASA
No ASA ASA
69% RR 69% RR
40 p<0.001 p=0.012
28.8%
(17.1-43.1)
Gastric ulcers, %

30
21.9%
(15.5-29.3)
20
8.9%
6.7% (3.0-19.6)
10 (3.2-11.9)

0
PN200 Naproxen PN200 Naproxen
n=150 n=151 n=56 n=52

Data shown are % (CI)

NS
NS
 Secondary endpoint: survival analysis of
incidence of duodenal ulcers at 6 months - ITT

PN200 EC naproxen
(n=206) (n=203)

Survival analysis, % (CI)

1 month 0.5 (0.1-3.4) 5.4 (3.0-9.6)
3 months 0.5 (0.1-3.4) 8.9 (5.5-14.2)
6 months** 0.5 (0.1-3.4) 10.8 (6.8-16.8)

**p<0.001, RR 95%
 Safety and tolerability

Proportion of patients, n (%) PN200 EC naproxen p

(n=206) (n=203)

Any UGI AE 105 (51.0) 144 (70.9) <0.001

Any UGI AE related to study drug 86 (41.7) 133 (65.5) <0.001
Dyspeptic symptoms* 17 (8.3) 18 (8.9) NS
Use of antacid rescue medication 145 (70.4) 170 (83.7) 0.001
UGI AEs leading to discontinuation 9 (4.4) 22 (10.8) 0.012

*upper abdominal pain, dyspepsia, eructation, gastric discomfort

 Conclusions
z Compared with EC naproxen, PN200
was associated with significantly
fewer gastric ulcers
fewer duodenal ulcers

z Concomitant low dose aspirin therapy

had no significant effect on the
gastric ulcer incidence