TinT AMITRMM JoIIRNM or tiAsrRorNH not om
`‘98., No. 12. 2003
`Vol.
`15331 000279270/03/33000
`<5: 2003 by Am. Coll. of Gastroenterology
`
`Published by Elsevier inc. doi:10.10lo/j.amjgastroenterol.200309.053
`
`Gastric Acid Control With Esomeprazole,
`Lansoprazole, Omeprazole, Pantoprazole, and
`Rabeprazole: A Five-Way Crossover Study
`
`Philip Miner, Jr, lVl,.D., Philip 0. Katz, M.D., Yusong Chen, Ph.D., and Mark Sostek, MD.
`
`Oklahoma Foundation/or Digestive Research, University of Oklahoma Health Sciences Center, Oklahoma
`City, Oklahoma; Department of Medicine, Graduate Hospilal, Philadelphia; and Divisions ofBioslatisties
`and Clinical Research, AstraZeneca, LP, Wilmington, Delaware
`
`OBJECTIVES: Proton pump inhibitors owe their clinical ef-
`ficacy to their ability to suppress gastric acid production.
`The objective of this study was to evaluate and compare
`intragastric pH following standard doses of esomeprazole,
`lansoprazole, omepraxole, pantoprazole and rabeprazolc.
`
`METHODS: This randomized, open—label. comparative five—
`way crossover study evaluated the 24-h intragastric pH profile
`of oral esomeprazole 40 mg, lansoprazole 30 mg, omeprazole
`20 mg, pantoprazole 40 mg, and rabeprazole 20 mg once daily
`in 34 Helieobaeter pylori—negative patients aged 18—60 yr
`with symptoms of gastroesophageal reflux disease. Patients
`were randomly assigned to one of five treatment sequences
`and study drug was taken on 5 consecutive mornings 30
`minutes prior to a standardized breakfast. A washout period
`of at least 10 days separated each treatment phase.
`
`RESULTS: Thirty—four patients provided evaluable data for
`all five comparators. The mean number of hours of evalu-
`able pH data was 223.75 hours. On day 5, intragastric pH
`was maintained above 4.0 for a mean of 14.0 h with esome—
`
`prazole, 12.1 h with rabeprazole, 11.8 h with omeprazole,
`l 1.5 h with lansoprazole, and 10.1 h with pantoprazole (p 5
`0.001 for differences between esomeprazole and all other
`comparators). Esomeprazole also provided a significantly
`higher percentage of patients with an intragastric pH greater
`than 4.0 for more than 12 11 relative to the other proton pump
`inhibitors ([7 < WE). The frequency of adverse events was
`similar between treatment groups.
`
`
`
`CONCLUSIONS: asomeprazole at the standard dose of 40
`mg once daily provided more effective control of gastric
`acid at steady state than standard doses of lansoprazole,
`omeprazole, pantoprazole. and rabeprazole in patients
`with symptoms ot’gastroesophageal reflux disease. (Am J
`Gastroenterol 2003;98:2616—2620. © 2003 by Am. Coll.
`of Gastroenterology)
`
`INTRODUCTlON
`
`Proton pump inhibitors (I’I’Is) owe their clinical efficacy to
`their ability to inhibit ll l
`, K ' adenosine triphosphatase in
`
`gastric parietal cells, resulting in suppression of gastric acid
`secretion ( I). The amount of time that intragastric pH is
`greater than 4.0 is a parameter that is frequently used to
`evaluate the pharmacodynamics and clinical effects of treat—
`ment with PPls in patients with acid—related diseases (2~5).
`Moreover, clinical investigations have confirmed that mu-
`cosal healing rates in erosive esophagitis can be correlated
`with the duration for which intragastric pH is maintained
`above 4.0 (6).
`Previously the effects of PMS on intragastric pH have
`been investigated in single-comparator studies (2,7). This
`trial was designed to compare the intragastric acid-suppres-
`sive phannacodynamics of standard doses of the five PPls
`currently available in the United States; esomeprazole, lan—
`soprazole, omeprazole, pantoprazole and rabeprazole. This
`study is the first published comparative pharmacodynamic
`trial to use a 5-way crossover design and provide the same
`controlled conditions across all treatment groups.
`
`MATERIALS AND METHODS
`
`single—center, open—label, multiple-dose,
`A randomized.
`five—way crossover study was conducted at one center in the
`United States in accordance with the ethical principles of the
`Declaration of Helsinki and Good Clinical Practice guide—
`lines. The study was approved by the local
`institutional
`review board at the University of Oklahoma Health Sci—
`ences Center and all patients provided signed informed
`consent. The randomization scheme was computer gener—
`ated. A centralized allocation method was used to assign
`patients to a treatment group. The choice of treatment se—
`quences was determined by balanced Latin square.
`
`Patients
`
`Men and women aged 18 ~60 yr, who experienced heartburn
`for an average of at least 2 days per month during the 2
`months before screening were eligible for enrollment. For
`those patients with a history of more frequent heartburn
`(three or more heartburn episodes per week during the 3
`months before study entry}, esophagogastroduodenoscopy
`was performed if no such evaluation had been performed
`
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`

`AJG — December, 2003
`
`Crossover Study with PPls
`
`2617
`
`within 6 months before study entry. Patients with past or
`present endoscopic evidence of esophageal erosions, ulcer,
`or any other significant upper GI pathology were excluded
`from participation. A rapid urease test by gastric biopsy to
`detect Helicobacrer pylori was also performed at the time of
`esophagogastroduodcnoscopy. All other patients underwent a
`13C02 urea breath test (Merete t, Nashville, TN}. Only patients
`who were H. pylori negative were eligible for enrollment.
`Women of childbearing potential were required to use
`acceptable birth control met‘rods. Exclusion criteria were
`pregnancy,
`lactation, any c.inically significant abnormal
`laboratory values at entry, or a history of a clinically sig—
`nificant medical disease. In addition, patients were excluded
`from the trial if they smoked or consumed nicotine—contain-
`ing products of any kind wi hin 3 months before the first
`dose of study drug or during t re study; if they consumed any
`alcoholic beverage or an average of more than four cups of
`coffee or caffeine-containing beverages per day within 1 wk
`before the first dose of study drug or during the study; or if
`they required chronic anti-inflammatory doses of aspirin
`and/or nonsteroidal anti—inflammatory drugs. Patients were
`also excluded if they had any history of drug or alcohol
`dependence, multiple drug allergies, or other drug-associ—
`ated adverse events. Discontinuation of any previous PPI
`therapy was required at least 10 days before randomization.
`No antiseeretory drugs, including HZ—receptor antagonists
`(prescription strength), prokinetic drugs, or any other agents
`known to alter the pharmacokinctics of PPls were allowed
`during the study or within 2 wk before entry.
`
`
`
`Study Procedures
`Each patient received either esomeprazole 40 mg, lansopra—
`zole 30 nrg, omeprazole 20 mg, pantoprazole 40 mg, or
`rabeprazole 20 mg orally once daily, 30 min before a stan—
`dardized breakfast for 5 consecutive days during each of the
`five treatment periods. Each dose of study drug was placed
`in an opaque envelope and given to the patient by a study
`coordinator who observed emptying of the study drug into
`the patient’s mouth and swallowing of the dose. Patients
`were prohibited from examining the study drugs. A starr-
`dardized breakfast was provided to the patients 30 minutes
`following each dose of study drug and patients were dis-
`missed from the clinic after they had been observed eating
`the breakfast. A maximum of six tablets of Gelusil‘é‘? (Pfizer
`Inc, Canada) per day was permitted for heartburn rescue
`therapy as needed, except after midnight on day 4 through
`the end of each treatment period. Patients were domiciled at
`the single investigational site during day 5, when 24-h
`intragastric pH monitoring was conducted and standardized
`meals provided. Each treatment period was separated by a
`washout period of 210 days, during which no PPI was
`taken. This was considered sufficient to avoid any carry—
`over effects on either gastric acid production or hepatic
`enzyme activity from the previous drug. The treatment
`periods were based around a repeated two-week schedule
`with the study drug being started and stopped, and the pi]
`
`study being conducted on the same day of the week. If a
`patient was unable to attend the clinic one week, they came
`back on the same day the following week resulting in
`washout periods of l0, 17 or 24 days.
`An ambulatory 24—h intragastric pH recording was per-
`formed beginning on day 5 of each treatment period. A
`calibrated microelectrode attached to a Medtronics Digitrap-
`per pll data logger (Medtronics, Minneapolis, MN) was
`positioned 10 cm below the manometrically located lower
`esophageal sphincter and used to evaluate intragastric pll
`every 4 s. Study drug was administered after probe place-
`ment on day 5 of each treatment period. All pll traces were
`blinded and assessed for evaluability by a single gastroen—
`tcrologist, independent of the principal investigator.
`The primary phannacodynamic endpoint of this study
`was the amount of a 24-h period that intragastric pH was
`maintained above 4.0 by each of the study drugs on day 5 of
`treatment. Twenty-four hour mean pH on day 5 was deter-
`mined for each treatment group. The percentage of subjects
`who had more than 12 h of intragastric pH greater than 4.0
`on day 5 was also determined.
`For the assessment of tolerability, all patients were en-
`couraged to report adverse events spontaneously or in re—
`sponse to general questioning. Routine laboratory screening,
`which included hematology, clinical chemistry, and urinal—
`ysis, was conducted at the screening visit and at the termi—
`nation of the study and monitored for any clinically signif—
`icant changes.
`
`Statistical rifethods
`
`Pharmacodynamic analyses were performed for evaluable
`patients who received all doses in each of the five treatment
`periods, and who, for each treatment phase, had at least 17 h
`of pll data within the reference range (>05 to <10.()) and
`not more than one continuous hour outside of this range.
`The percentage of time and number of hours (of the 24-h
`interval} with a pH greater than 4.0 on day 5 were analyzed
`with a mixed model with effects for subject, period, and
`treatment, in which subject was a random effect. The least
`square mean and SEM for each treatment was directly
`calculated. Statistical comparisons were performed with
`analysis of variance. A similar model was developed to
`evaluate the percentage of subjects with intragastric pH
`greater than 4.0 for more than 12 h. The OR for each pair of
`comparators was calculated, along with the 95% Cls. P
`values were determined with the )(2 test. Similarly, for each
`comparison of mean 24—h intragastric pIi between esome—
`prazole and other PPIs, the least square mean, SEM, 95%
`Cls, and p value were determined. A p value less than 0.05
`was considered significant.
`Safety assessments were recorded and tabulated for all
`patients who received at least one dose of study drug.
`
`Sample Siz)
`It was estimated that 30 evaluable patients would be re—
`quired to provide 95% overall power to detect a difference
`
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`

`2618
`
`Miner et at.
`
`AJG — Vol. 98. No. 12, 2003
`
`1. Baseline Demographic and Clinical Characteristies
`Table
`(Evaluable Cohort; N I 34)
`Characteristic
`
`Value
`
`(‘14:)
`
`Gender, 11
`Male
`Female
`Age of)
`
`Mean (SD)
`Range
`Race. n (%)
`Caucasian
`Other
`Height (cm)
`Mean (81))
`Range
`Weight (kg)
`Mean (SD)
`Range
`Body mass index (kg/1112)
`29.4 (5.1)
`Mean (SD)
`19.2 39.5
`Range
`23 (67.6)
`History of heartburn >3 times/wk
`
`during the last 3 mo, 11
`(0/0)
`
`8 (23.5)
`26 (76.5)
`
`44.1 (11)
`20762
`
`31 (91.2)
`3 (8.8)
`
`167.6 (8.5)
`1524—1880
`
`83.2 (18.1)
`44.5 125.8
`
`of 12.4% between esomeprazole 40 mg once daily and any
`one of the other four PPI treatments, assuming the within-
`patient SD to be 10.5 and the significance level to be 0.05.
`The trial was designed to randomize 45 patients to compen-
`sate for an expected 33% dropout rate. or non—evaluable rate
`due to the complexity of trial methodology and stringent
`requirements for evaluability.
`
`RESULTS
`
`Forty—five patients were randomized to form the intent—to—
`treat and safety cohorts. The first patient entered the study
`on December 4, 2001, and the last patient completed the
`study on June 23, 2002. Eleven patients were excluded from
`the evaluable group. Two withdrew consent. Three discon-
`tinued because 01“ adverse events.
`in the remaining six
`patients. their pH measurements were not evaluable because
`of miscalibration (one patient), Digitrapper failure (one pa—
`tient), premature removal of the pH probe (one patient), or
`a p11 outside the reference range for more than 1 continuous
`
`20
`
`
`
`5: 11.9001
`-3.
`:
`P < 0.0001
`P-omm
`'________.. ___..._n_. ._ -M ,e_._,_3_ WW_. _]
`A —l
`'
`l
`9-0001
`
`Table 2. The Mean Number 01‘ Hours of pH Data for Each Treat—
`ment Group
`
`Mean (SD);
`
`hours
`Treatment
`11
`Range; hours
`
`
`233472386
`23.85 (0.09)
`34
`Esomeprazole
`212572386
`23.77 (0.31)
`34
`Lansoprazole
`23 27 23.86
`2384(011)
`34
`Omcprarolc
`23 ‘73~23.8t)
`23.86 (0.02)
`34
`Pantoprazole
`
`Rabeprazole
`34
`23.75 (0.59)
`20 40723.86
`
`hour (three patients). Evaluable traces for all five PPls were
`required for a patient to be considered in the efficacy anal-
`yses.
`
`Table 1 summarizes the baseline demographic and clin—
`ical characteristics of the 34 patients in the evaluable cohort.
`Approximately three quarters of the patients were women,
`and the majority had a history of three or more episodes of
`heartburn per week during the 3 months before screening.
`Of the 136 washout periods (four for each patient), most
`were 10 days (11 : l 13), although some were 17 (n .— 20)
`or 24 (n = 3) days. Table 2 summarizes the mean number
`ot‘hours of evaluable pll data for each treatment group. 01‘
`the 170 evaluable traces, although the protocol considered
`>17 hours of data acceptable. only one trace contained less
`than 22 hours data. The mean number of hours of pH data
`for each treatment group ranged between 23.75 and 23.86.
`The mean number of hours for each treatment group that
`intragastric pll was greater than 4.0 on day 5 is shown in
`Figure 1. Treatment with esomeprazole provided signifi=
`cantly more hours with intragastn'c pll greater than 4.0,
`compared with all other PPls.
`The percentage of time on day 5 that intragastric pH was
`greater than 4.0 and the mean 24—h intragastric pl] for each
`treatment group are shown in Table 3. There was a statis-
`tically significant difference between esomcprazole and all
`of the other PPIs for the percentage of the 24-h period that
`intragastric p11 was greater than 4.0 and for mean p11.
`The percentage of patients with intragastric pH greater
`than 4.0 for more than 12 h is presented in Figure 2. A
`significantly higher percentage of patients treated with es—
`omeprazolc had intragastric p11 greater than 4.0 for more
`than 12 11 relative to treatment with all other I’PIs. Compar—
`
`
`
`Table 3. Percent Time (Least Square Mean) That Intragastric pH
`Was 4.0 and Mean 24—Hr lntragastric pH on Day 5 by Treatment
`
`Group (N = 34)
`
`Mean pH
`% Time pH
`Treatment
`‘> 4.0 (SHM)
`(SFM)
`
`5343* (3.13)
`Esoineprazole 40 mg
`4114-) (11.15)
`50.53 (3.38)
`3.70 (11.17)
`Rahcprazolc 20 mg
`3.54 (0.17)
`49.16 (3.38)
`Omeprazole 20 mg
`Lansoprazole 30 mg
`3.56 (0.15)
`47.98 (3.26)
`
`41.94 {3.19)
`333 10.17)
`Pantoprazole 40 mg
`* )1 1'5 0.0001 for comparison 01‘ esomepramle imam; lansopramle. omepramle. and
`pantoprazole; p ' 0.001 for comparison between esomeprazole and rabepramle.
`% )1} <1 0.0001 for comparison of esnmepramle vumm lansupra/nle. onieprazole.
`and pantoprazolc; p
`0.003 for comparison between esnmcprazole and ralucprazolc.
`
`...10UI
`
`VI
`
`0 rHoursintragastrtcpH>441
`
`
`. I , I . I , I
`
`Esomeprazole
`
`Rabeprazote
`
`Omeprazole
`
`Lansoprazole
`
`Panmprazole
`
`Figure 1. Mean number of hours on day 5 that intragastrie pH was
`>40 by treatment group (N = 34).
`
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`

`AJG A December, 2003
`
`Crossover Study with PPls
`
`2613
`
`
`
`Until now, it has been difficult to compare the pharma—
`codynamic properties of each of these five PPIs directly
`because previous trial designs involved a single comparator.
`The five—way crossover study that we performed provided
`an opportunity for a direct comparison between I’I’Is. These
`results support those from the single-comparator studies,
`which showed that esorneprazole 40 mg provided more
`effective control of gastric acid than omeprazole 40 mg on
`days 1 and 5, as measured by the mean percentage of a 24—h
`pe‘iod that intragastric pH was greater than 4.0 (2). In other
`sttdies using single comparators, standard-dose esomepra-
`7.0 e maintained intragastric p11 greater than 4.0 for a longer
`pe‘centage of a 24-h period at day 5 than did standard doses
`of lansoprazole, pantoprazole, or rabeprazole (7).
`n our study, esomeprazole maintained intragastric pH
`greater than 4.0 on day 5 for 58.4% of the 24-h period. In
`otl er studies, the percentage of a 24—h interval that intra—
`gastric pH was greater than 4.0 after 5 days of esomeprazole
`rat ged between 57.7% and 69.8% (2, 7—9) . Although this
`na‘row range might in part be attributable to less interpatient
`va iability, as assessed by the area under the plasma con-
`centration—time curve with esomeprazole compared with
`omeprazole (8), it also emphasizes the importance of head-
`o—head comparisons within one and the same study.
`There are limitations to this study. Although an open—
`abel design is standard practice for p11 studies, this corn—
`narrative crossover study would ideally have a double—blind
`nethodology. However, introducing a double—blind design
`would have required over—encapsulation, which could affect
`dissolution, bioavailability and other pharmaeokinetic pa—
`‘ameters of the study drugs. We did adopt a “masked dos—
`ing" technique that ensured patients were blinded to the
`study drug they took on any particular occasion.
`Although our study did not investigate the effect of the
`five I’I’Is on any clinical endpoints, small studies with ci-
`metidinc and/or omeprazole have correlated duration and
`degree of esophageal acid exposure with clinical endpoints
`such as healing of esophageal erosions (13, 14). Other
`authors have also suggested that a clear relationship exists
`between the degree of esophageal acid exposure and healing
`of erosive esophagitis (6, 15). The more effective gastric
`acid—suppressive
`pharrnacodynamics
`of
`esomeprazole
`might contribute to its improved clinical efficacy compared
`with other PPls. In well—designed clinical trials, esornepra—
`zole 40 mg once daily produced significantly higher rates of
`
`
`
`
`, ,7 ,
`7W—__._.
`
`PIOD!
`moms
`"m
`
`E 100
`A
`:—
`a 90
`80«
`
`8q
`
`
`
`home
`
`
`
`
`.
`
`Esomeprazola
`
`Rabaprazole
`
`Omoprazola
`
`r
`
`r
`
`LaII soprazole
`
`Panwprazole
`
`9.
`5 1o —
`u.
`§ 60
`3,
`so -
`404
`2 3r
`g 20 4
`10
`0
`
`‘ g
`
`8a
`
`S:
`
`g
`
`Figure 2. Percent of subjects with intragastric pH >40 for >12
`hours (N I 34).
`
`isons between the other pairs of PPIs did not reach statistical
`significance; all showed efficacy comparable to each other
`for this parameter.
`The number and frequency of adverse events, serious
`adverse events, and diseontinuations due to adverse events
`are presented in Table 4. There were four serious adverse
`events, none considered treatment-related, but two resulted
`in study withdrawal. A third patient withdrew because of a
`nonserious adverse event (nausea). The types of adverse
`events that were observed were similar to those previously
`reported and most frequently included headache, nausea,
`diarrhea. flatulence, or abdominal pain.
`
`DISCUSSION
`
`All five PI’Is investigated in our study provided gastric acid
`suppression (pll>4) for at
`least 10 hours in a 24 hour
`period. Esomeprazole (40 mg once daily) provided an in-
`tragastric pl'l greater than 4.0 for a significantly greater
`amount of a 24-h period at steady state (day 5) compared
`with standard—dose lansoprazole. omeprazole, pantoprazole,
`or rabeprazole in patients with symptoms of gastroesopha-
`geal reflux disease. Similarly,
`the percentage of patients
`with an intragastric pH greater than 4.0 for more than 12 h
`was significantly greater with esomeprazole relative to the
`other I’Pls. Although the study was not specifically designed
`to detect differences in this parameter between the other
`pairs of PPIs, no statistical differences were found. For all
`efficacy endpoints, the results were numerically lowest with
`pantoprarcole, although statistically the differences were
`only significant compared with esomeprazole.
`
`Table 4. Adverse Events and Discontinuations Because of Adverse Events
`
`Rabeprazole
`l’antoprazole
`Lansoprazole
`()meprazole
`Esomeprazole
`40 mg
`20 mg
`30 mg
`40 mg
`20 mg
`
`(n i 42)
`(n i 38)
`{n i 39)
`(n i 41)
`(n i 43)
`
`Any AF.
`Treatment-related AB
`Serious AE
`Discontinuation of study treatment
`because of AE
`
`Data are presented as n ('34)). Al".
`
`adverse events.
`
`16138.1)
`7 (16.7)
`l {2.4)
`2 (4.8)
`
`1406.8)
`7 (18.4)
`0(0)
`0 (0)
`
`17 (43.6)
`8 (20,5)
`‘2 (51)
`t) (0)
`
`23 (56.1)
`14 (34.1)
`0 (0)
`{l (0)
`
`19 (41.4.2)
`
`6 (144.0)
`l (2.3)
`l (2.3)
`
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`

`2620
`
`Miner et at.
`
`AJG — Vol. 98, No. 12, 2003
`
`healing and symptom resolution in patients with erosive
`esophagitis relative to lansoprazole 30 mg or omeprazole 20
`mg once daily 00712).
`llowever, a large well—designed
`study that investigated the relationship between the phar-
`macodynamic endpoints we describe and clinical endpoints
`relevant to GERD would be desirable.
`
`In summary, this randomized, five-way crossover trial
`demonstrated that standard—dose esomeprazolc (40 mg once
`daily) suppresses intragastric acid production for a greater
`amount of a 24—h period in patients with symptoms of
`gastroesophageal reflux disease than do standard doses of
`other PPls.
`
`ACKNOWLEDGMENTS
`
`The authors would like to acknowledge Christopher Rains,
`Karen van lloeven, and Caroline Spencer For their assis—
`tance with manuscript preparation.
`
`
`Reprint requests and correspondence: Philip Miner, Jr_, MD_,
`Oklahoma Foundation for Digestive Research, University ofOkla—
`honia Health Sciences Center. 7ll Stanton L. Young Boulevard,
`Suite 6197 Oklahoma City. OK 73104.
`Received May 1’4, 2003; accepted Sep. 30, 2003.
`
`REFERENCES
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`l‘ll’i‘cct ol' csoniepra—
`2. Rohss K. Hassclgrcn G. Hedcnsttom H.
`Zole 40 mg vs omeprazole 40 mg on 24-hour intragastric pH
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`Dig Dis Sci 2002;47:954—8,
`3. Franco MT, Salvia G, Terrin G. et al. LansopraVole in the
`treatment of gastro—oesophageal reflux disease in childhood.
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`Kata PO, Hallebakk JG, Castell DO. Gastric acidity and acid
`breakthrough with twice—daily omeprazole or lansoprazole.
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`Aliment Pharmacol Ther 3000;14:70944.
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