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`OMEPRAZOLE VS. MISOPROSTOL FOR ULCERS ASSOCIATED WITH NONSTEROIDAL ANTIINFLAMMATORY DRUGS
`
`OMEPRAZOLE COMPARED WITH MISOPROSTOL FOR ULCERS ASSOCIATED
`WITH NONSTEROIDAL ANTIINFLAMMATORY DRUGS
`
`.D.,
`, P
` S
`, M.B., B.S., L
` A. K
`, D.M., J
` J. H
`C
`H
`ZCZEPAÑSKI
`ESZEK
`ARRASCH
`EFFREY
`AWKEY
`HRISTOPHER
` G. W
`, M.B., B.S., A
` B
`, M.D., C.M., A
` J. S
`, M.B.,
`D
`NTHONY
`LAN
`ALKER
`ONALD
`ARKUN
`WANNELL
` N
` D. Y
`, M.D.,
`AND
`EVILLE
`EOMANS
`
` NSAID-I
` U
` M
` M
`ISOPROSTOL
`FOR
`NDUCED
`LCER
`ANAGEMENT
`
`FOR
`
`
`
`THE
`
` O
`MEPRAZOLE
`
`
`
`VERSUS
`
` (OMNIUM) S
`TUDY
`
` G
`ROUP
`
`*
`
`A
`BSTRACT
`Background
`Misoprostol is effective for ulcers as-
`sociated with the use of nonsteroidal antiinflamma-
`tory drugs (NSAIDs) but is often poorly tolerated
`because of diarrhea and abdominal pain. We com-
`pared the efficacy of omeprazole and misoprostol
`in healing and preventing ulcers associated with
`NSAIDs.
`Methods
`In a double-blind study, we randomly as-
`signed 935 patients who required continuous NSAID
`therapy and who had ulcers or more than 10 ero-
`sions in the stomach or duodenum (or both) to re-
`ceive 20 mg or 40 mg of omeprazole orally in the
`morning or 200
`g of misoprostol orally four times
`m
`daily. Patients were treated for four weeks or, in the
`absence of healing, eight weeks. Treatment success
`was defined as the absence of ulcers and the pres-
`ence of fewer than five erosions at each site and not
`more than mild dyspepsia. We then randomly reas-
`signed 732 patients in whom treatment was success-
`ful to maintenance therapy with 20 mg of omepra-
`zole daily, 200
`g of misoprostol twice daily, or
`m
`placebo for six months.
`Results
`At eight weeks, treatment was successful
`in 76 percent of the patients given 20 mg of omep-
`razole (233 of 308), 75 percent of those given 40 mg
`of omeprazole (237 of 315), and 71 percent of those
`given misoprostol (212 of 298). The rates of gastric-
`ulcer healing were significantly higher with 20 mg of
`omeprazole (but not 40 mg of omeprazole) than with
`misoprostol. Healing rates among patients with duo-
`denal ulcers were higher with either dose of omep-
`razole than with misoprostol, whereas healing rates
`among patients with erosions alone were higher
`with misoprostol. More patients remained in remis-
`sion during maintenance treatment with omeprazole
`(61 percent) than with misoprostol (48 percent,
`⫽
`P
`0.001) and with either drug than with placebo (27
`⬍
`percent, P
`0.001). There were more adverse events
`during the healing phase in the misoprostol group
`than in the groups given 20 mg and 40 mg of omep-
`razole (59 percent, 48 percent, and 46 percent, re-
`spectively).
`Conclusions
`The overall rates of successful treat-
`ment of ulcers, erosions, and symptoms associated
`with NSAIDs were similar for the two doses of omep-
`razole and misoprostol. Maintenance therapy with
`omeprazole was associated with a lower rate of re-
`lapse than misoprostol. Omeprazole was better tol-
`erated than misoprostol. (N Engl J Med 1998;338:
`727-34.)
`©1998, Massachusetts Medical Society.
`
`N
`
`ONSTEROIDAL antiinflammatory drugs
` but have
`(NSAIDs) are widely used
`1,2
`substantial gastroduodenal toxicity and
`account for 21 to 25 percent of reported
`adverse reactions in patients taking these drugs in
`combination with other medications.
` Epidemio-
`3,4
`logic studies have estimated that the risks of gastrop-
`athy and death are 3 to 10 times as high
`among
`5-10
`patients who take NSAIDs regularly as among those
`who do not, and endoscopic studies have shown that
`the prevalence of peptic ulcers is 20 to 30 percent
`
`among regular users of NSAIDs.
`11
`Hitherto, the most effective approach to ulcer
`prophylaxis has used misoprostol to replace the cy-
`toprotective prostaglandins that NSAIDs deplete
`from the gastroduodenal mucosa.
` However, mi-
`12-15
`soprostol is often poorly tolerated because of diar-
`rhea and abdominal pain. An alternative approach is
`to protect the gastroduodenal mucosa by suppress-
`ing acid secretion. Acid has an important permissive
`role in NSAID-associated mucosal injury.
` Most
`16
`NSAIDs are weak acids
` that selectively concentrate
`17
`in the mucosa at low intragastric pH, enhancing the
`diffusion of acid from the lumen to the mucosa and
`potentiating mucosal injury.
` Elevation of the in-
`18-21
`tragastric pH to 4 or higher with omeprazole mark-
`edly reduces acute NSAID-associated mucosal inju-
` The profound acid suppression induced by
`ry.
`22,23
`proton-pump inhibitors may represent a mechanism
`by which the slowing of ulcer healing associated
`with concurrent use of NSAIDs and histamine H
`-
`2
`receptor antagonists can be overcome.
` We com-
`24,25
`pared an antisecretory strategy using omeprazole
`with a cytoprotective strategy using misoprostol in
`patients taking long-term NSAIDs.
`
`From the Division of Gastroenterology, University Hospital, Notting-
`ham, United Kingdom (C.J.H.); the Peninsula Specialist Centre, Kippa
`Ring, Australia (J.A.K.); the Department of Rheumatology, University
`Medical School, Lublin, Poland (L.S.); Sunshine Coast Day Surgery, Ma-
`roochydore, Australia (D.G.W.); the Division of Gastroenterology, Montre-
`al General Hospital, Montreal (A.B.); the Rheumatology Unit, City Hos-
`pital, Nottingham, United Kingdom (A.J.S.); and the Department of
`Medicine, University of Melbourne, Western Hospital, Melbourne, Austral-
`ia (N.D.Y.). Address reprint requests to Dr. Hawkey at the Nottingham
`Gastrointestinal Trials Service, Division of Gastroenterology, University
`Hospital, Nottingham NG7 2UH, United Kingdom.
`*Other participants in the OMNIUM Study are listed in the Appendix.
`
`Volume 338 Number 11
`
`ⴢ
`
`727
`
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`MYLAN PHARMS. INC. EXHIBIT 1060 PAGE 1
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`

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`The New England Journal of Medicine
`
`METHODS
`
`Study Design and Recruitment
`The study was an international, double-blind, randomized
`comparison of the efficacy, tolerability, and safety of omeprazole
`and misoprostol as healing or maintenance treatments for patients
`receiving long-term treatment with NSAIDs. The study was ap-
`proved by the ethics committees of the participating centers and
`conducted in 14 countries (93 centers) from April 1992 to April
`1995 in accordance with the principles of good clinical practice
`26
`and the Declaration of Helsinki (Tokyo amendments). The study
`was conducted in two phases: a healing phase and a maintenance
`phase, each of which included three double-blind parallel treat-
`ment groups.
`
`Healing Phase
`
`Patients of either sex who were 18 to 85 years of age and who
`had any condition requiring continuous treatment with oral or
`rectal NSAIDs above a predetermined minimal dose (there was
`no maximal dose) underwent endoscopy after providing informed
`consent. The minimal (and mean) daily oral doses of the com-
`monly used NSAIDs were 50 mg (129 mg) for diclofenac, 100
`mg (137 mg) for ketoprofen, and 500 mg (844 mg) for naprox-
`en. Patients who were found to have any or all of the following
`were invited to enter the study by giving further written informed
`consent: ulcer, defined as a mucosal break at least 3 mm in diam-
`eter with definite depth in the stomach, duodenum, or both;
`more than 10 gastric erosions; and more than 10 duodenal ero-
`sions. The main exclusion criteria were concurrent reflux esoph-
`agitis at stage 3 or 4 according to the Savary–Miller classification,
`clinically important upper gastrointestinal bleeding, pyloric steno-
`sis, a history of gastric surgery, or gastrointestinal disorders that
`might impair the absorption of the study drugs. Patients could
`enter the study if they were taking glucocorticoids at a dose
`10
`⭐
`mg of prednisolone (or its equivalent).
`Patients continued to take NSAIDs and were randomly as-
`signed (in blocks of three at each site) to receive 20 mg or 40 mg
`of omeprazole (Losec, Astra Hässle, Mölndal, Sweden) once daily
`in the morning or 200
`g of misoprostol (Cytotec, Searle, Skokie,
`m
`Ill.) four times daily. All drugs were given orally. The patients un-
`derwent endoscopy after four weeks of treatment and again at
`eight weeks if the lesions were not healed. The primary end point
`in this phase was treatment success (defined before the study be-
`gan as the absence of ulcers in the stomach or duodenum and the
`presence of fewer than five gastric erosions, fewer than five duo-
`denal erosions, and not more than mild symptoms of dyspepsia).
`Erosions were assessed with a modified Lanza scale used in pre-
`vious studies
`; clinically significant healing of erosions corre-
`27,28
`sponded to a 2-point reduction in the Lanza grade (from a grade
`of 4, defined as the presence of more than 10 erosions, to a grade
`of 2, defined as the presence of fewer than 5 erosions). Patients
`without this level of healing at eight weeks received open treat-
`ment with 40 mg of omeprazole daily for a further four to eight
`weeks. We also assessed the healing rates of all ulcers, larger ulcers
`(
`5 mm), gastric ulcers, duodenal ulcers, and erosions, and
`⭓
`changes in dyspeptic symptoms and the quality of life.
`
`Maintenance Phase
`
`Patients in whom treatment was successful during the healing
`phase were randomly assigned on a 2:2:1 basis (in blocks of five
`at each site) to receive 20 mg of omeprazole once daily, 200
`g
`m
`of misoprostol twice daily, or placebo. Randomization was not
`formally balanced according to treatment assignment in the heal-
`ing phase. Patients were followed for six months or until the pri-
`mary end point, treatment failure (defined before the study began
`as the development of any of the following: an ulcer, more than
`10 gastric erosions, more than 10 duodenal erosions, at least
`moderate symptoms of dyspepsia, or adverse events resulting in
`the discontinuation of treatment). We also assessed the rates of
`
`728
`
`ⴢ
`
`March 12, 1998
`
`relapse of all ulcers, larger ulcers, gastric ulcers, duodenal ulcers,
`and erosions and the quality of life. When a patient withdrew
`from the study, both randomized treatment and assessment of its
`effectiveness ceased.
`
`Assessments
`The patients were assessed clinically and endoscopically month-
`ly during the healing phase and at one, three, and six months dur-
`ing the maintenance phase or as clinically required. Antral
`Heli-
`
`cobacter pylori status was determined at base line with the urease
`enzyme test (CLO test, Delta West, Bentley, Australia). Patients
`
`
`infected with H. pylori were not treated for this infection, because
`there was no evidence that treatment was beneficial
` and be-
`29,30
`cause
`–stimulated mucosal synthesis of prostaglandin
`H. pylori
`may be beneficial for NSAID-associated ulcers.
` Biopsies of gas-
`31
`tric ulcers were performed to rule out the possibility of malignant
`conditions. We assessed compliance by counting the number of
`tablets or capsules the patients returned.
`At each assessment the patients were asked whether they had
`had specific dyspeptic symptoms (epigastric or abdominal pain,
`heartburn, nausea, vomiting, upper abdominal bloating, and an
`empty feeling in the stomach) during the preceding seven days
`and to describe any upper gastrointestinal symptoms they had on
`the day of the visit. These symptoms were graded at each visit as
`absent, mild (easily tolerated), moderate (interfering with normal
`activities), or severe (incapacitating; leaving the patient unable to
`perform normal activities). During the first four weeks of the
`study, the patients also completed symptom diary cards recording
`the presence or absence of epigastric or abdominal pain and
`heartburn during the day and at night.
`Safety assessments were based on the reported symptoms, ad-
`verse events, and the results of standard blood screening. Quality
`of life was assessed at 73 centers in nine countries. Each patient
`completed three questionnaires — the Nottingham Health Profile,
`the Psychological General Well-Being Index, and the Gastrointes-
`tinal Symptom Rating Scale — at entry and monthly during the
`healing phase and after one and six months of maintenance treat-
`ment (or when treatment was discontinued). The Nottingham
`Health Profile evaluates the perceived effect of chronic disease in
`terms of a patient’s emotions, ability to sleep, social isolation, en-
`ergy level, level of pain, and level of mobility.
` The scores can
`32
`range from 0 (no problem or distress) to 100 (worst possible
`problem or distress). The Nottingham Health Profile also evalu-
`ates, in a “yes” or “no” format, the effect of health-related prob-
`lems on the patient’s work, home life, social life, sex life, and lei-
`sure activities. The Psychological General Well-Being Index
`measures subjective well-being or distress in terms of anxiety, de-
`pressed mood, positive well-being, self-control, and general health
`and vitality on a 6-point Likert scale.
` The worst possible score is
`33
`22, and the best possible is 132. The Gastrointestinal Symptom
`Rating Scale assesses indigestion, reflux, constipation, abdominal
`pain, and diarrhea on a 7-point Likert scale.
` A mean item value
`34
`is calculated in which a score of 1 indicates no bothersome symp-
`toms and a score of 7 extremely bothersome symptoms.
`
`Statistical Analysis
`We compared the overall rates of treatment success and healing
`of specific lesions during the healing phase using a Mantel–
`Haenszel life-table test with data obtained at four and eight
`weeks. We performed multiple logistic-regression analysis of prog-
`nostic factors that may have influenced the success of treatment
`at four weeks: treatment, base-line lesion, ulcer size,
`
`H. pylori sta-
`tus at base line, blood group, type of arthritic disease, smoking
`status, age, and sex. Symptom scores recorded at four weeks, strat-
`ified according to severity at base line, were compared with use of
`Wilcoxon’s test, and diary-card scores with use of Student’s t-test.
`The length of time until treatment failure during the maintenance
`phase was compared by the log-rank test. Possible prognostic fac-
`tors were assessed by the Cox proportional-hazards regression
`method. In each phase of the study, changes in the scores of the
`
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`MYLAN PHARMS. INC. EXHIBIT 1060 PAGE 2
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`OMEPRAZOLE VS. MISOPROSTOL FOR ULCERS ASSOCIATED WITH NONSTEROIDAL ANTIINFLAMMATORY DRUGS
`
`quality-of-life assessments from base line to the most recent visit
`were compared between treatment groups with an unpaired t-test.
`The study was designed to investigate the two doses of omep-
`razole and misoprostol as separate treatments and to have 80 per-
`cent power to detect differences between any of the three treat-
`ments at a level of 0.017 (with Bonferroni’s correction) on the
`basis of estimated relapse rates during the maintenance phase of
`60 percent in the placebo group, 35 percent in the misoprostol
`group, and 20 percent in the omeprazole group. The primary ef-
`ficacy analysis used an intention-to-treat approach that included
`all patients meeting major entry criteria who took at least one
`dose of medication. The safety analysis included all patients who
`received at least one dose of medication and for whom there were
`safety data, regardless of whether they met the entry criteria for
`the trial. For these reasons there were small differences in the
`numbers of patients included in the efficacy and safety analyses.
`No interim analyses were conducted. For cases in which data cen-
`soring, arising from the use of life-table analysis, prevented valid
`statistical comparisons of subgroups, P values are not presented.
`
`RESULTS
`Characteristics of the Patients
`A total of 935 patients were enrolled in the heal-
`ing phase, of whom 921 had efficacy data that could
`
`be evaluated. Of 732 patients enrolled in the main-
`tenance phase, 725 had efficacy data that could be
`evaluated. In the healing phase, seven patients who
`did not use NSAIDs, three who had no ulcers and
`10 erosions, and four with major deviations from
`⭐
`the inclusion criteria could not be evaluated. In the
`maintenance phase, two patients who received no
`trial drug, one whose treatment was unknown, one
`with major deviations from the inclusion criteria,
`and three who declined to continue the study could
`not be evaluated.
`The treatment groups were well balanced with re-
`gard to demographic characteristics, underlying dis-
`eases, and
`status (Table 1) and, in the
`H. pylori
`maintenance phase, with regard to treatment re-
`ceived during the healing phase (data not shown).
`The most commonly used NSAIDs at entry were di-
`clofenac (23 percent of the patients), naproxen (22
`percent), and ketoprofen (16 percent). Approxi-
`mately two thirds of the patients were enrolled in
`the study because of ulcers, two thirds of which were
`
`OF
`
`IN
`
` E
` A
`THE
`FFICACY
`
`.*
`NALYSIS
`
`T
`ABLE
`
` 1.
`
`B
`-L
`ASE
`INE
`
` C
`
`HARACTERISTICS
`
`
`
` P
`THE
`
` I
`ATIENTS
`
`
`NCLUDED
`
`
`
`C
`HARACTERISTIC
`
`H
`EALING
`
` P
`HASE
`
`,
`
`OMEPRAZOLE
`20 mg/
`DAY
`(
`308)
`⫽
`N
`
`,
`
`OMEPRAZOLE
`40 mg/
`DAY
`(
`315)
`⫽
`N
`
`,
`
`MISOPROSTOL
`200
`g
`m
`
`
`TIMES
`DAILY
`(
`298)
`⫽
`N
`
`4
`
`M
`AINTENANCE
`
` P
`HASE
`,
`MISOPROSTOL
`200
`g
`m
`
`TWICE
`DAILY
`(
`296)
`⫽
`N
`
`,
`
`OMEPRAZOLE
`20 mg/
`DAY
`(
`274)
`⫽
`N
`
`63
`
`58
`23–79
`
`83
`73
`19
`42
`
`78
`29
`6
`
`37
`
`23
`
`4
`
`36
`
`60
`
`58
`23–85
`
`83
`70
`23
`41
`
`75
`27
`7
`
`42
`
`20
`
`2
`
`36
`
`PLACEBO
`(
`155)
`⫽
`N
`
`69
`
`57
`20–80
`
`80
`71
`23
`38
`
`78
`31
`9
`
`39
`
`18
`
`6
`
`37
`
`65
`
`58
`23–85
`
`59
`
`58
`20–85
`
`65
`
`59
`23–84
`
`83
`73
`20
`34
`
`78
`27
`8
`
`38
`
`19
`
`5
`
`38
`
`81
`71
`23
`41
`
`75
`27
`8
`
`42
`
`21
`
`2
`
`35
`
`82
`68
`25
`43
`
`76
`33
`8
`
`42
`
`20
`
`5
`
`33
`
`Female sex (%)
`Age (yr)
`Mean
`Range
`Mean weight (kg)
`Men
`Women
`Smoker (%)
`–positive (%)
`H. pylori
`Previous gastrointestinal
`disease (%)
`Dyspepsia
`Peptic ulcer
`Bleeding
`Current gastrointestinal
`lesions (%)
`Gastric ulcer with or without
`erosions
`Duodenal ulcer with or
`without erosions
`Gastric ulcer and duodenal
`ulcer with or without
`erosions
`Erosions only
`Disease requiring NSAIDs (%)
`Rheumatoid arthritis
`Osteoarthritis
`Others
`Combinations
`Psychological General Well-
`Being Index
`Gastrointestinal Symptom
`Rating Scale
`
`38
`46
`12
`4
`1.3
`92.9
`⫾
`
`39
`48
`11
`2
`1.3
`91.3
`⫾
`
`37
`48
`13
`2
`1.3
`94.2
`⫾
`
`39
`47
`12
`2
`1.3
`98.8
`⫾
`
`40
`48
`10
`2
`1.3
`101
`⫾
`
`36
`45
`16
`3
`1.9
`97.6
`⫾
`
`0.05
`2.14
`⫾
`
`2.09
`0.05
`⫾
`
`2.03
`0.05
`⫾
`
`1.70
`0.04
`⫾
`
`1.65
`0.04
`⫾
`
`1.76
`0.06
`⫾
`
`*Plus–minus values are means
`
`⫾
`
`SE.
`
`Volume 338 Number 11
`
`ⴢ
`
`729
`
`
`
`
`
`MYLAN PHARMS. INC. EXHIBIT 1060 PAGE 3
`
`

`

`
`
`
`
`
`The New England Journal of Medicine
`
`gastric; 83 percent of all ulcers were 5 mm or more
`in diameter. Most patients had rheumatoid arthritis
`or osteoarthritis.
`
`Healing Phase
`Treatment Success
`During the eight weeks of the healing phase, the
`rates of treatment success were similar among the
`group given 20 mg of omeprazole (76 percent [233
`of 308 patients], P⫽0.76 for the comparison with 40
`mg of omeprazole), the group given 40 mg of omep-
`razole (75 percent [237 of 315]), and the group giv-
`en misoprostol (71 percent [212 of 298], P⫽0.37
`for the comparison with 20 mg of omeprazole and
`P⫽0.24 for the comparison with 40 mg of omepra-
`zole). When the rates of treatment success were ana-
`lyzed to include as treatment failures all patients
`whose data could not be evaluated the respective rates
`were 75 percent, 75 percent, and 71 percent.
`At eight weeks, healing of gastric ulcers was sig-
`nificantly more common among patients treated
`with 20 mg of omeprazole (87 percent [102 of 117
`patients]) than among those given misoprostol (73
`percent [91 of 125], P⫽0.004) (Fig. 1). The heal-
`ing rate for 40 mg of omeprazole was 80 percent
`(105 of 132 patients, P⫽0.14 for the comparison
`with misoprostol). The healing rates for 20 mg of
`omeprazole, 40 mg of omeprazole, and misoprostol
`were 85 percent (111 of 131 patients), 79 percent
`(111 of 140), and 74 percent (104 of 141), respec-
`tively, when patients with concurrent gastric and
`duodenal ulcers were included and 88 percent (78
`of 89 patients), 78 percent (83 of 107), and 72 per-
`cent (71 of 99), respectively, when patients with
`gastric ulcers of 5 mm or more in diameter were
`
`analyzed. The rates of healing of duodenal ulcers
`were also significantly higher in the groups given 20
`mg of omeprazole (93 percent [55 of 59 patients])
`or 40 mg of omeprazole (89 percent [58 of 65])
`than in the group given misoprostol (77 percent [46
`of 60], P⬍0.001 for each comparison) (Fig. 1). A
`similar pattern of results was seen when patients
`with concurrent gastric ulcers initially were included
`in the analysis — 93 percent (68 of 73 patients), 89
`percent (65 of 73), and 79 percent (60 of 76), re-
`spectively — as well as in the analysis of duodenal
`ulcers that were 5 mm or more in diameter: 94
`percent (47 of 50 patients), 89 percent (48 of 54),
`and 77 percent (44 of 57), respectively. By contrast,
`erosions healed significantly better during the eight
`weeks with misoprostol (87 percent [84 of 97 pa-
`tients]) than with 20 mg of omeprazole (77 percent
`[91 of 118], P⬍0.001) or 40 mg of omeprazole (79
`percent [86 of 109], P⫽0.01) (Fig. 1).
`Treatment was judged unsuccessful in few patients
`at eight weeks because of the persistence of at least
`moderate symptoms of dyspepsia alone: five patients
`in the group given 20 mg of omeprazole (1.6 per-
`cent), two in the group given 40 mg of omeprazole
`(0.6 percent), and three in the group given miso-
`prostol (1.0 percent). Therefore, the major reason
`for treatment failure was lack of healing of ulcers or
`erosions.
`
`Prognostic Factors
`The favorable prognostic factors were the pres-
`ence of duodenal ulcers (P⫽0.04) or erosions alone
`(P⫽0.05) at base line rather than gastric ulcers, and
`a positive test (vs. a negative test) for H. pylori
`(P⫽0.05). At eight weeks, the respective rates of
`
`Gastric Ulcers
`20 mg of omeprazole
`100
`
`Duodenal Ulcers
`40 mg of omeprazole
`
`Erosions
`Misoprostol
`100
`
`100
`
`80
`
`60
`
`40
`
`20
`
`0
`
`Healing (%)
`
`80
`
`60
`
`40
`
`20
`
`0
`
`0
`
`80
`
`60
`
`40
`
`20
`
`0
`
`0
`
`4
`Week
`
`8
`
`47/59
`
`57/65
`
`36/60
`
`55/59
`
`58/65
`
`46/60
`
`4
`Week
`
`8
`
`65/118
`
`91/118
`
`67/109
`
`86/109
`
`73/97
`
`84/97
`
`0
`
`4
`Week
`
`8
`
`88/132
`
`105/132
`
`NO. OF PATIENTS HEALED/TOTAL NO.
`102/117
`20 mg of
`82/117
`omeprazole
`40 mg of
`omeprazole
`Misoprostol
`
`77/125
`
`91/125
`
`Figure 1. Cumulative Rates of Healing of Gastric Ulcers, Duodenal Ulcers, and Erosions at Four and Eight Weeks during
`Treatment with 20 mg of Omeprazole Daily, 40 mg of Omeprazole Daily, or 200 mg of Misoprostol Four Times Daily.
`
`730
`
`ⴢ
`
`March 12, 1998
`
`
`
`
`
`MYLAN PHARMS. INC. EXHIBIT 1060 PAGE 4
`
`

`

`OMEPRAZOLE VS. MISOPROSTOL FOR ULCERS ASSOCIATED WITH NONSTEROIDAL ANTIINFLAMMATORY DRUGS
`
`Maintenance Phase
`
`Relapse
`Kaplan–Meier estimates of the rates of remission
`during the maintenance phase are shown in Figure
`2. The estimated proportion of patients in remission
`at six months was 61 percent among those taking 20
`mg of omeprazole, as compared with 48 percent
`among those taking 200 mg of misoprostol twice
`daily (P⫽0.001) and 27 percent among those tak-
`ing placebo (P⬍0.001 for the comparisons with
`omeprazole and misoprostol).
`Thirty-two percent of patients taking placebo (50
`of 155) had gastric ulcers at relapse, as compared
`with 10 percent of patients taking misoprostol (31
`of 296) and 13 percent of those taking omeprazole
`(35 of 274). The respective rates of ulcers of 5 mm
`or more in diameter at relapse were 20 percent (31
`of 155 patients), 8 percent (23 of 296), and 8 per-
`cent (21 of 274). Duodenal ulcers developed in 12
`percent of patients given placebo (19 of 155), as
`compared with 10 percent of those given misopros-
`tol (30 of 296) and 3 percent of those given omep-
`razole (7 of 274). The respective rates for ulcers that
`were 5 mm or more in diameter were 10 percent (15
`of 155 patients), 9 percent (26 of 296), and 3 per-
`cent (7 of 274). Fourteen percent of patients taking
`placebo (21 of 155), 7 percent of those taking mi-
`soprostol (21 of 296), and 12 percent of those tak-
`ing omeprazole (34 of 274) had multiple erosions
`at relapse. The site and nature of the lesion at relapse
`tended to be the same as those at base line. Of the
`
`Omeprazole
`
`Misoprostol
`
`Placebo
`
`0
`
`42
`
`6 8 10 12 14 16 18 20 22 24
`Week
`
`26
`
`100
`
`80
`
`60
`
`40
`
`20
`
`0
`
`Patients in Remission (%)
`
`NO. AT RISK OF RELAPSE
`Omeprazole
`274
`Misoprostol
`296
`Placebo
`155
`
`253
`252
`130
`
`203
`193
`69
`
`149
`129
`41
`
`Figure 2. Kaplan–Meier Estimates of the Rates of Remission
`among Patients Treated with 20 mg of Omeprazole Daily, 200
`mg of Misoprostol Twice Daily, or Placebo for up to 26 Weeks.
`P⬍0.001 for the comparison of omeprazole with placebo by the
`log-rank test, and P⫽0.001 for the comparison of omeprazole
`with misoprostol by the log-rank test.
`
`Volume 338 Number 11
`
`ⴢ 731
`
`
`
`
`
`treatment success among H. pylori–negative patients
`and H. pylori–positive patients were 74 percent (112
`of 151 patients) and 69 percent (80 of 116) in the
`group given misoprostol, 73 percent (132 of 181)
`and 83 percent (79 of 95) in the group given 20 mg
`of omeprazole, and 70 percent (117 of 167) and 83
`percent (95 of 114) in the group given 40 mg of
`omeprazole.
`
`Dyspeptic Symptoms
`The proportion of patients with moderate-to-
`severe symptoms of dyspepsia after four weeks of
`treatment declined from 38 percent (at base line) to
`11 percent in the misoprostol group, from 45 per-
`cent to 11 percent in the group given 20 mg of
`omeprazole (P⫽0.08 for the comparison with mi-
`soprostol), and from 45 percent to 6 percent in the
`group given 40 mg of omeprazole (P⫽0.004 for
`the comparison with misoprostol and P⫽0.25 for
`the comparison with 20 mg of omeprazole). Diary-
`card data also showed that patients had significantly
`less abdominal pain with omeprazole than with mi-
`soprostol. Abdominal pain was reported on a mean
`(⫾SE) of 43⫾2 percent of days with 20 mg or 40
`mg of omeprazole, as compared with a mean of 50⫾2
`percent of days with misoprostol (P⫽0.02 for both
`comparisons). Heartburn was recorded on 16⫾1
`percent of days with 20 mg of omeprazole and
`14⫾1 percent of days with 40 mg of omeprazole, as
`compared with 29⫾2 percent of days with miso-
`prostol (P⬍0.001 for both comparisons).
`
`Quality-of-Life Evaluation
`Quality-of-life evaluations were completed by 212
`patients in the group given 20 mg of omeprazole,
`209 patients in the group given 40 mg of omep-
`razole, and 185 patients in the misoprostol group.
`Patients treated with 20 mg of omeprazole had sig-
`nificantly greater improvements in scores on the
`Gastrointestinal Symptom Rating Scale than patients
`treated with misoprostol: total score, ⫺0.47 as com-
`pared with ⫺0.20 (P⬍0.001); reflux score, ⫺0.82 as
`compared with ⫺0.33 (P⬍0.001); abdominal-pain
`score, ⫺0.69 as compared with ⫺0.35 (P⬍0.001);
`and indigestion score, ⫺0.48 as compared with
`⫺0.30 (P⫽0.04). The 40-mg dose of omeprazole
`was associated with significant improvement in the
`total score (⫺0.36, P⫽0.008 for the comparison
`with misoprostol) and the reflux score (⫺0.75, P⬍
`0.001 for the comparison with misoprostol). Pa-
`tients treated with misoprostol had worsening diar-
`rhea scores (⫹0.22), in contrast to those treated
`with 20 mg of omeprazole (⫺0.24, P⬍0.001) or 40
`mg of omeprazole (⫺0.06, P⬍0.001). The sleep
`score on the Nottingham Health Profile improved
`more with misoprostol than with 20 mg of omepra-
`zole (⫺8.6 as compared with ⫺3.1; P⫽0.03). There
`were no other significant differences between groups.
`
`MYLAN PHARMS. INC. EXHIBIT 1060 PAGE 5
`
`

`

`The New England Journal of Medicine
`
`patients with gastric ulcers at relapse, 73 percent had
`gastric ulcers at presentation. The respective values
`for duodenal ulcers and erosions were 72 percent
`and 61 percent.
`
`Prognostic Factors Influencing Remission
`Factors associated with a higher probability of
`continued remission were treatment with omepra-
`zole rather than misoprostol (P⫽0.005) or placebo
`(P⬍0.001), the presence of erosions alone at base
`line (P⫽0.05), nonsmoking status (P⫽0.001), and
`a positive test for H. pylori (P⫽0.03). The estimated
`proportions of H. pylori–positive patients and H. py-
`lori–negative patients in remission at six months
`were 74 percent and 54 percent, respectively, in the
`omeprazole group, 44 percent and 52 percent in the
`misoprostol group, and 27 percent and 28 percent
`in the placebo group.
`
`Quality-of-Life Evaluation
`Quality-of-life evaluations were completed by 188
`patients in the omeprazole group, 193 patients in
`the misoprostol group, and 95 patients in the place-
`bo group. The mean values for the following scores
`on the Gastrointestinal Symptom Rating Scale im-
`proved in the omeprazole group and worsened
`in the misoprostol group: total score, ⫺0.06 as
`compared with ⫹0.15 (P⬍0.001); reflux score,
`⫺0.04 as compared with ⫹0.35 (P⬍0.001); abdom-
`inal-pain score, ⫺0.15 as compared with ⫹0.08 (P⫽
`0.003); and indigestion score, ⫺0.10 as compared
`with ⫹0.12 (P⫽0.008). Placebo was associated with
`worse scores than omeprazole for control of abdom-
`inal pain (score, ⫹0.12 as compared with ⫺0.15; P⫽
`0.007) and reflux (⫹0.36 as compared with ⫺0.04;
`P⫽0.002) and better scores than misoprostol for
`controlling diarrhea (⫺0.09 as compared with ⫹0.12;
`P⫽0.04).
`
`Safety and Adverse Events
`During the healing phase, more patients in the
`misoprostol group (59 percent [175 of 299]) re-
`ported adverse events than in the group given 20 mg
`of omeprazole (48 percent [148 of 311]) or the
`group given 40 mg of omeprazole (46 percent [147
`of 319]). More patients in both phases stopped tak-
`ing misoprostol because of adverse events or a lack
`of efficacy (Table 2). A perforated duodenal ulcer
`developed in one patient during the maintenance
`phase after 31 days of placebo. She underwent sur-
`gery and recovered.
`
`DISCUSSION
`Our study was designed to compare omeprazole
`and misoprostol at standard recommended doses as
`healing and prophylactic treatments for patients tak-
`ing NSAIDs. The rates of treatment success with 20
`mg or 40 mg of omeprazole daily were similar to
`
`732 ⴢ March 12, 1998
`
`TABLE 2. INCIDENCE OF MODERATE-TO-SEVERE ADVERSE EVENTS
`IN ALL PATIENTS AND REASONS FOR DISCONTINUATION OF
`TREATMENT AND FOLLOW-UP IN PATIENTS INCLUDED IN THE
`EFFICACY ANALYSIS.
`
`VARIABLE
`
`HEALING PHASE
`
`OMEPRAZOLE,
`20 mg/DAY
`(N⫽311)
`
`OMEPRAZOLE,
`40 mg/DAY
`(N⫽319)
`
`MISOPROSTOL,
`200 mg
`4 TIMES DAILY
`(N⫽299)
`
`39
`
`38
`
`35
`
`4.5
`1.9
`1.6
`1.3
`
`2.9
`2.3
`9.9
`
`4.8
`
`5.1
`
`5.3
`3.1
`1.3
`1.6
`
`1.9
`1.6
`10.6
`
`5.6
`
`5.0
`
`11.4
`8.0
`3.7
`2.7
`
`1.0
`1.3
`16.9
`
`9.9
`
`7.0
`
`MAINTENANCE PHASE
`MISOPROSTOL,
`200 mg TWICE
`DAILY
`(N⫽297)
`
`OMEPRAZOLE,
`20 mg/DAY
`(N⫽275)
`
`134
`
`116
`
`PLACEBO
`(N⫽155)
`
`85
`
`7.6
`5.1
`4.4
`2.5
`2.2
`2.5
`
`12.1
`
`3.9
`8.2
`
`8.4
`4.7
`3.4
`3.4
`2.7
`3.4
`
`16.8
`
`7.7
`9.1
`
`4.5
`5.8
`3.2
`3.2
`4.5
`0.6
`
`10.3
`
`1.9
`8.4
`
`Mean duration of expo-
`sure to drug (days)
`Most common adverse
`events (% of patients)
`Diarrhea
`Abdominal pain
`Flatulence
`Respiratory tract infec-
`tion
`Headache
`Arthritis
`Discontinuation of treat-
`ment (% of patients)
`Adverse event or lack of
`efficacy
`Other reasons*
`
`Mean duration of expo-
`sure to drug (days)
`Most common adverse
`events (% of patients)
`Diarrhea
`Abdominal pain
`Arthritis
`Flatulence
`Pain
`Respiratory tract infec-
`tion
`Discontinuation of treat-
`ment (% of patients)
`Adverse event
`Other reasons†
`
`*The main other reason was unwillingness to continue in the study (four
`patients in the group given 20 mg of omeprazole, eight in the group given
`40 mg of omeprazole, and seven in the misoprostol group).
`†The main other reason was unwillingness to continue in the study (11
`patients in the omeprazole group, 10 in the misoprostol group, and 8 in
`the placebo group).
`
`that with 200 mg of misoprostol four times daily
`during the healing phase, but 20 mg of omeprazole
`daily was more effective than 200 mg of misoprostol
`twice daily in the maintenance phase and was better
`tolerated in both phases. The 20-mg dose of omep-
`razole was associated with better quality-of-life scores
`on the Gastrointestinal Symptom Rating Scale and
`fewer withdrawals from treatment. The 40-mg dose
`of omeprazole (75 percent rate of treatment success)
`offered no additional healing benefit over that af-
`
`
`
`
`
`MYLAN PHARMS. INC. EXHIBIT 1060 PAGE 6
`
`

`

`OMEPRAZOLE VS. MISOPROSTOL FOR ULCERS ASSOCIATED WITH NONSTEROIDAL ANTIINFLAMMATORY DRUGS
`
`forded by the 20-mg dose, but it resulted in slightly
`better scores on some assessments of symptoms. In
`an attempt to replicate clinically important dilem-
`mas, we studied patients with clinically significant le-
`sions at initial endoscopy, who are at higher risk for
`ulcers than those without lesions.2