Medical treatments for the maintenance therapy of reflux
`oesophagitis and endoscopic negative reflux disease (Review)
`
`Donnellan C, Preston C, Moayyedi P, Sharma N
`
`This is a reprint of a Cochrane review, prepared and maintained by The Cochrane Collaboration and published in The Cochrane Library
`2004, Issue 4
`
`http://www.thecochranelibrary.com
`
`Medical treatments for the maintenance therapy of reflux oesophagitis and endoscopic negative reflux disease (Review)
`Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
`
`Page 1 of 58
`
`Patent Owner Ex. 2055
`Mylan v. Pozen
`IPR2017-01995
`
`

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`T A B L E O F C O N T E N T S
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`ABSTRACT .
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`PLAIN LANGUAGE SUMMARY
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`BACKGROUND .
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`OBJECTIVES
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`METHODS .
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`RESULTS .
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`DISCUSSION .
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`AUTHORS’ CONCLUSIONS
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`ACKNOWLEDGEMENTS
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`REFERENCES .
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`CHARACTERISTICS OF STUDIES
`DATA AND ANALYSES .
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`6
`13
`15
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`24
`53
`
`Medical treatments for the maintenance therapy of reflux oesophagitis and endoscopic negative reflux disease (Review)
`Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
`
`i
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`Page 2 of 58
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`Patent Owner Ex. 2055
`Mylan v. Pozen
`IPR2017-01995
`
`

`

`[Intervention Review]
`
`Medical treatments for the maintenance therapy of reflux
`oesophagitis and endoscopic negative reflux disease
`
`Clare Donnellan2, Cathy Preston3, Paul Moayyedi1, Nav Sharma4
`
`1Department of Medicine, Division of Gastroenterology, McMaster University, Hamilton, Canada. 2Gastroenterology, University of
`Leeds, Leeds, UK. 3Gastroenterology, St James University Hospital, Leeds, UK. 4Gastroenterology Unit, Queen Elizabeth Hospital,
`Birmingham, UK
`
`Contact address: Paul Moayyedi, Department of Medicine, Division of Gastroenterology, McMaster University, Room 4W8E, 1200
`Main Street West, Hamilton, Ontario, L8N 3Z5, Canada. moayyep@mcmaster.ca.
`
`Editorial group: Cochrane Upper Gastrointestinal and Pancreatic Diseases Group.
`Publication status and date: Edited (no change to conclusions), published in Issue 1, 2009.
`Review content assessed as up-to-date: 3 August 2004.
`
`Citation: Donnellan C, Preston C, Moayyedi P, Sharma N. Medical treatments for the maintenance therapy of reflux oesophagi-
`tis and endoscopic negative reflux disease. Cochrane Database of Systematic Reviews 2004, Issue 4. Art. No.: CD003245. DOI:
`10.1002/14651858.CD003245.pub2.
`
`Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
`
`Background
`
`A B S T R A C T
`
`Gastro-oesophageal reflux disease (GORD) - reflux of stomach contents +/- bile into the oesophagus causing symptoms such as
`heartburn and acid reflux - is a common relapsing and remitting disease which often requires long-term maintenance therapy. Patients
`with GORD may have oesophagitis (inflammation of the oesophagus) or a normal endoscopy (endoscopy negative reflux disease or
`ENRD).
`
`Objectives
`
`To assess the effects of continuous maintenance therapy in adults with GORD (both ENRD and healed oesophagitis).
`
`Search strategy
`
`We searched Cochrane Central Register of Controlled Trials (The Cochrane Library Issue 2, 2003), MEDLINE (1966 to 2003),
`EMBASE (1980 to 2003), CINAHL (1982-2003), and the National Research Register (Issue 2, 2003) and reference lists of articles.
`We also contacted manufacturers and researchers in the field.
`
`Selection criteria
`
`Randomised controlled studies comparing PPIs, H2RAs, prokinetics, sucralfate and combinations either in comparison to another
`treatment regimen or to placebo in adults with reflux oesophagitis and ENRD.
`
`Data collection and analysis
`
`One author extracted data from included trials and a second author carried out an unblinded check. Two authors independently assessed
`trial quality. Study authors were contacted for additional information.
`
`Medical treatments for the maintenance therapy of reflux oesophagitis and endoscopic negative reflux disease (Review)
`Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
`
`1
`
`Page 3 of 58
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`Patent Owner Ex. 2055
`Mylan v. Pozen
`IPR2017-01995
`
`

`

`Main results
`
`Maintenance of patients with healed oesophagitis:
`
`For a healing dose of PPI (generally the standard dose given by the manufacturer) versus placebo, the relative risk (RR) for oesophagitis
`relapse was 0.26 (95% confidence interval (CI) 0.19 to 0.36); versus H2RAs the RR was 0.36 (95% CI 0.28 to 0.46) and versus
`maintenance PPIs the RR was 0.63 (95% CI 0.55 to 0.73). However overall adverse effects were also more common and headaches
`were more common when comparing healing PPIs to H2RAs.
`
`For a maintenance dose of PPI (half of the standard dose) versus placebo, the RR for oesophagitis relapse was 0.46 (95% CI 0.38 to
`0.57) and versus H2RAs the RR was 0.57 (95% CI 0.47 to 0.69). Overall adverse effects were more common.
`
`H2RAs were of marginal help but beneficial for symptomatic relief. Prokinetics and sucralfate were also more effective than placebo.
`
`For ENRD patients:
`
`Limited data with one RCT showed benefit for omeprazole 10 mg once daily over placebo (RR 0.4; 95% CI 0.29 to 0.53).
`
`Authors’ conclusions
`
`The findings in this review support the long-term treatment of oesophagitis to prevent relapse, both endoscopically and symptomatically.
`Healing doses of PPIs are more effective than all other therapies, although there is an increase in overall adverse effects compared to
`placebo, and headache occurrence compared to H2RAs. H2RAs prevent relapse more effectively than placebo, demonstrating a role
`for PPI-intolerant patients. Prokinetics and sucralfate both show benefit over placebo, but the former is no longer licenced. There is
`only limited data for ENRD.
`
`P L A I N L A N G U A G E S U M M A R Y
`
`Medical treatments for the maintenance therapy of reflux oesophagitis and endoscopic negative reflux disease
`
`Gastro-oesophageal reflux disease (GORD) is a common disease. GORD is usually due to acid and bile refluxing through the lower
`oesophageal sphincter and produces symptoms of heartburn, acid regurgitation, and less commonly chest and abdominal pain. The main
`treatments available concentrate on reducing acid secretion by proton pump inhibitors (PPIs) and H2 receptor antagonists (H2RAs),
`increasing the pressure at the lower oesophageal sphincter, enhancing gastric emptying with prokinetics and protecting mucosa from
`acid damage with sucralfate.
`
`This review is a systematic review of randomised controlled trials examining the efficacy of continuous PPIs, H2RAs, prokinetic therapy
`and sucralfate in the maintenance therapy of reflux oesophagitis and endoscopy negative reflux disease. While intermittent or ’on-
`demand’ therapy is increasingly being used, it is not covered by the scope of this review.
`
`The findings of this review support the long-term treatment of oesophagitis to prevent relapse. Healing doses of PPIs are more effective
`than all other therapies, although there is an increase in overall adverse effects compared to placebo, and headache occurrence compared
`to H2RAs. H2RAs prevent relapse more effectively than placebo, demonstrating a role for PPI-intolerant patients. Prokinetics and
`sucralfate both show benefit over placebo, but the former is no longer licenced.
`
`B A C K G R O U N D
`
`Gastro-oesophageal reflux disease (GORD) is a common disease
`with an estimated prevalence of 20% in the adult American pop-
`ulation (Sonnenberg 1999) and similar rates in Europe.
`
`GORD is primarily attributable to acid and bile refluxing through
`the lower oesophageal sphincter (Armstrong 1999) and produces
`symptoms of heartburn, acid regurgitation, and less commonly
`chest and abdominal pain. The main treatments available concen-
`trate on reducing acid secretion by proton pump inhibitors (PPIs)
`
`Medical treatments for the maintenance therapy of reflux oesophagitis and endoscopic negative reflux disease (Review)
`Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
`
`2
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`Page 4 of 58
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`Patent Owner Ex. 2055
`Mylan v. Pozen
`IPR2017-01995
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`and H2 receptor antagonists (H2RAs), increasing the pressure at
`the lower oesophageal sphincter, enhancing gastric emptying with
`prokinetics and protecting mucosa from acid damage with sucral-
`fate.
`
`Endoscopic examination is a common investigation for patients
`with GORD (Navaratham 1998). When endoscopy is undertaken
`a majority of patients have normal findings (endoscopy negative
`reflux disease or ENRD) with the remainder having oesophageal
`inflammation (oesophagitis).
`
`The efficacy of medical therapy in acute management of oe-
`sophagitis has been the subject of other reviews and ENRD acute
`management has been evaluated in a previous Cochrane Review
`(van Pinxteren 2000). GORD is a chronic relapsing condition with
`significant impact on quality of life (Scott 1999). GORD symp-
`toms recur rapidly on discontinuation of therapy therefore mainte-
`nance therapy is central to management of the condition (Williams
`1997). There are currently only limited systematic reviews assess-
`ing maintenance therapy in the treatment of oesophagitis and none
`assessing ENRD.
`
`GORD affects a significant number of patients who present for
`treatment and place a burden on healthcare budgets (Chiba 1997).
`Primary and secondary care physicians are faced with a variety of
`treatment options. Randomised controlled trials suggest that PPIs
`are the most effective acute healing treatment (Earnest 1999) but
`the actual relative efficacy of each drug in the maintenance ther-
`apy for reflux oesophagitis and ENRD is uncertain. An accurate
`assessment of this would inform clinical decision making. Efficacy
`is not the only aspect of the decision making process as cost of
`therapy also needs to be considered (Dent 1999). Nevertheless, a
`more precise estimate of relative efficacy would help establish the
`most cost-effective therapy for maintenance of reflux oesophagitis
`and ENRD patients.
`
`This review is a systematic review of randomised controlled tri-
`als examining the efficacy of continuous PPIs, H2RAs, prokinetic
`therapy and sucralfate in the maintenance therapy of reflux oe-
`sophagitis and endoscopy negative reflux disease. While intermit-
`tent or ’on-demand’ therapy is increasingly being used, it is not
`covered by the scope of this review.
`
`O B J E C T I V E S
`
`(1) To assess the efficacy of PPIs (at different doses), H2RAs,
`prokinetic therapy, sucralfate and combinations compared to each
`other and placebo in preventing relapse of mucosal inflammation
`in patients with oesophagitis.
`
`(2) To assess the efficacy of PPIs (at different doses), H2RAs, proki-
`netic therapy, sucralfate and combinations compared to each other
`and placebo in and preventing relapse of symptoms in patients
`with ENRD and oesophagitis.
`
`(3) To compare the incidence of adverse effects associated with the
`different treatments.
`
`M E T H O D S
`
`Criteria for considering studies for this review
`
`Types of studies
`
`Randomised controlled trials assessing maintenance therapy of re-
`flux oesophagitis and ENRD. Those studies assessing patients with
`’complicated reflux disease’ (i.e. those with oesophageal strictures
`or Barrett’s oesophagus) were excluded.
`
`Types of participants
`
`All patients were adults who had had an endoscopy. In the case
`of ENRD, the main presenting symptoms were heartburn and/or
`acid reflux. Patients with reflux oesophagitis at endoscopy (mu-
`cosal inflammation and/or mucosal breaks of the oesophagus) re-
`quired a repeat endoscopy to demonstrate healing after a course
`of therapy before entering into the maintenance phase of the trial.
`Any recognised grading of oesophagitis was acceptable and even
`if the oesophagitis was mild, patients were considered to have oe-
`sophagitis, rather than ENRD.
`
`Types of interventions
`
`The tested drug had to fall within the following drug classes a-
`d, the comparison regimen was also one of a-e. (Combinations of
`these were admissible for either arm).
`(1) PPIs: esomeprazole, lansoprazole, omeprazole, pantoprazole,
`rabeprazole.
`We defined healing dose of a PPI as the manufacturers standard
`dose of drug (i.e. omeprazole 20mg, lansoprazole 30mg, panto-
`prazole 40mg and rabeprazole 20mg all once daily) whilst mainte-
`nance therapy was half this dose (i.e. omeprazole 10mg, lansopra-
`zole 15mg, pantoprazole 20mg, rabeprazole 10mg). The excep-
`tion was esomeprazole which is an S-enantiomer of omeprazole (a
`racemic mixture of S and R enantiomers). As esomeprazole 20mg
`should be at least as effective as omeprazole 20mg we defined a
`healing dose of esomeprazole as 20mg once daily and a mainte-
`nance dose as 10mg daily. This is half the manufacturers standard
`dose but this decision was taken to reduce heterogeneity between
`trials by keeping the same chemical entity at the same dose.) Dou-
`ble dose was defined as double the standard dose (i.e. omeprazole
`40mg, esomeprazole 40mg).
`(2) H2RAs: cimetidine, famotidine, nizatidine, ranitidine (where
`results from different doses were pooled).
`(3) Prokinetic therapy: cisapride, domperidone, metoclopramide.
`
`Medical treatments for the maintenance therapy of reflux oesophagitis and endoscopic negative reflux disease (Review)
`Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
`
`3
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`Patent Owner Ex. 2055
`Mylan v. Pozen
`IPR2017-01995
`
`

`

`(4) Sucralfate
`(5) Placebo +/- antacid +/- no treatment
`Patients must have had at least 12 weeks of continuous therapy.
`
`Types of outcome measures
`
`Trials were included if they reported evidence of assessment at 12
`to 52 weeks.
`Primary outcomes varied according to the group evaluated. The
`primary outcomes in the reflux oesophagitis group were the pro-
`portion of patients in whom the oesophagitis had relapsed as well
`as the proportion of patients with significant symptoms. The pri-
`mary outcome in the ENRD group was the proportion with sig-
`nificant symptoms.
`Secondary outcomes assessed quality of life (standard mean differ-
`ence in scores) and adverse events/dropout rates (total number for
`each drug and individual symptoms of headache, diarrhoea and
`abdominal pain).
`
`Search methods for identification of studies
`
`We conducted a search to identify all published and unpublished
`randomised controlled trials (RCTs). We searched the follow-
`ing electronic databases: the Cochrane Central Register of Con-
`trolled Trials (CENTRAL), The Cochrane Library (Issue 2, 2003),
`MEDLINE (1966 to 2003), EMBASE (1980 to 2003), CINAHL
`(1982-2003) and the National Research Register (Issue 2, 2003).
`We handsearched reference lists from trials selected by electronic
`searching to identify further relevant trials. We also handsearched
`published abstracts from conference proceedings from the United
`European Gastroenterology Week (published in Gut) and Diges-
`tive Disease Week (published in Gastroenterology).
`We designed the search strategies for the review by using a com-
`bination of subject headings specific to each database’s syntax and
`text word phrases. The following search strategy was constructed
`by using a combination of subject headings and text words relat-
`ing to the symptoms of gastro-oesophageal reflux disease (GORD)
`and pharmacological interventions used for alleviating symptoms
`of the disease. We applied the standard Cochrane search strategy
`filter for identifying randomised controlled trials to all searches.
`MEDLINE search strategy
`exp esophagus/
`esophag$.tw.
`oesophag$.tw.
`exp gastroesophageal reflux/
`gastroesophageal adj3 reflux.tw.
`gastro adj3 oesophageal adj3 reflux.tw.
`gastro adj3 esophageal adj3 reflux.tw.
`gord.tw.
`gerd.tw.
`exp duodenogastric reflux
`exp bile reflux
`
`acid adj3 reflux.tw.
`gastric adj3 acid adj3 secret$.tw.
`stomach adj3 acid secret$.tw.
`gastric adj3 eros$.tw.
`stomach adj3 eros$.tw.
`exp heartburn
`heartburn.tw. or indigestion.tw.
`exp esophagitis
`esophagitis.tw.
`oesophagitis.tw.
`Endoscopy/ or Endoscopy, digestive system/ or Endoscopy, gas-
`trointestinal/
`endoscopy adj3 negative adj3 reflux.tw.
`enrd.tw.
`low$ adj6 sphincter$ adj3 pressur$.tw.
`les.tw.
`exp gastric emptying/
`exp gastroparesis/
`exp gastritis/
`gastr$ adj3 empt$ adj3 disorder$.tw.
`stomach adj3 empt$ adj3 disorder.tw.
`or/30-60
`exp proton pump/
`proton adj3 pump adj3 inhibitor$.tw.
`ppi.tw.
`exp omeprazole/
`omeprazole.tw.
`lansoprazole.tw.
`pantoprazole.tw.
`rabeprazole.tw.
`esomeprazole.tw
`exp histamine h2 antagonists/
`cimetidine.tw.
`exp cimetidine
`famotidine.tw.
`exp famotidine
`nizatidine.tw.
`exp nizatidine
`ranitidine.tw.
`exp ranitidine
`esomeprazole.tw.
`prokinetic adj3 agent$.tw.
`exp domperidone
`domperidone.tw.
`exp metoclopramide
`metoclopramide.tw.
`exp sucralfate/
`sucralfate.tw.
`exp anti ulcer agents
`anti adj3 ulcer adj3 agent$.tw.
`antiulcer adj3 agent$.tw.
`exp antacids
`
`Medical treatments for the maintenance therapy of reflux oesophagitis and endoscopic negative reflux disease (Review)
`Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
`
`4
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`Patent Owner Ex. 2055
`Mylan v. Pozen
`IPR2017-01995
`
`

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`antacid$.tw.
`aluminium adj1 hydroxide.tw.
`exp magnesium hydroxide
`magnesium adj1 hydroxide.tw.
`exp magnesium oxide
`magnesium adj1 oxide.tw.
`exp calcium carbonate
`calcium adj1 carbonate.tw.
`exp Magnesium Silicate
`magnesium adj1 silicate.tw.
`exp bismuth
`bismuth.tw.
`exp carbenoxolone
`carbenoxolone.tw.
`exp misoprostol
`misoprostol.tw.
`mucosa$ adj3 protect$ adj3 agent$.tw.
`hydrotalcite.tw.
`algicon.tw.
`alginates.tw.
`gaviscon.tw.
`maalox.tw.
`magnesium adj1 trisilicates.tw.
`sodium adj1 bicarbonate.tw.
`sodium adj1 carbonate.tw.
`116 or/62-115
`117 61 and 116
`118 117 and 29
`In addition, we contacted members of the Cochrane UGPD
`Group and pharmaceutical companies with an interest in gastroen-
`terology and asked them to supply details of any outstanding clin-
`ical trials and relevant unpublished materials.
`Bibliographies from trials selected by electronic searching were
`then handsearched to identify further relevant trials.
`
`Data collection and analysis
`
`Selection of studies
`The lead reviewer screened titles and trial abstracts that had been
`identified by the search strategy. A sample of 200 of these was then
`assessed independently. Two reviewers then screened the full article
`of selected trials to confirm eligibility, using pre-designed eligibility
`forms to assess quality. An adjudicator assessed any discrepancies.
`Data extraction
`One of the reviewers extracted data. A second reviewer checked
`these unblinded.
`We recorded the following features:
`- Setting: primary or secondary care
`- country of origin
`- method of randomisation: true versus pseudo, stated versus not
`
`stated
`- adequacy of allocation concealment: stated versus not stated
`- details of blinding of patients and outcome assessors: stated versus
`not stated, masked versus not masked
`- inclusion and exclusion criteria used
`- baseline comparability between treatment groups
`- treatments compared and number of patients in each arm
`- dropouts reported and their reasons
`- dose of drugs
`- grading system for oesophagitis (e.g. Savary-Miller, Los Angeles)
`- validated GORD questionnaires
`- adverse events: the total number reported and individual symp-
`toms of headache, abdominal pain and diarrhoea
`Data analysis
`All analysis was on intention to treat data and we considered re-
`flux oesophagitis and ENRD patients separately. The main out-
`comes being assessed were oesophagitis relapse (reflux oesophagitis
`patients), symptom control (reflux oesophagitis and ENRD) and
`adverse effects. We had initially planned to assess these at 3, 6 and
`12 months, but the individual RCTs provided data at different
`timepoints, therefore the final time point was used (with a max-
`imum of 52 weeks) as this gave us information with the longest
`follow-up. We also collected data on quality of life on the different
`interventions.
`We compared interventions, using placebo and combinations as
`described previously. We expressed the impacts of interventions
`as relative risks together with 95% confidence intervals. Analysis
`was repeated to obtain figures for risk difference and we calculated
`numbers of patients needed to treat (or harm) by 1/(risk differ-
`ence) and expressed with 95% confidence intervals. Meta-analysis
`was only attempted if there were sufficient trials of similar compar-
`isons reporting the same outcomes. Healing of oesophagitis was
`dichotomised into healed versus not healed and symptoms were
`dichotomised into no/minimal symptoms and significant symp-
`toms. Results were synthesised using the ’relative risk of relapse’
`of oesophagitis or symptoms, expressed with a 95% confidence
`interval. If significant heterogeneity was detected (p < 0.15), we
`investigated possible explanations by assessing the importance of
`the pre-defined factors listed in the protocol, using a random ef-
`fects model.
`The following features were prospectively evaluated, by meta-re-
`gression, to assess their effect on any observed outcomes as a cause
`for any heterogeneity:
`(1) Multi-centre versus single centre
`(2) Country of origin
`(3) Mean age of patients included in the study
`(4) Method of randomisation
`(5) Method of concealment of allocation
`(6) Masking versus no masking
`(7) Dose of drug
`(8) Different drugs in a specific class (e.g. omeprazole versus lan-
`soprazole)
`
`Medical treatments for the maintenance therapy of reflux oesophagitis and endoscopic negative reflux disease (Review)
`Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
`
`5
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`Mylan v. Pozen
`IPR2017-01995
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`

`

`(9) Duration of treatment
`(10) Severity of reflux oesophagitis included at study entry in the
`reflux oesophagitis group. The influence of the proportions of
`mild/ moderate and severe reflux oesophagitis in each study on
`the outcome was assessed. Mild/moderate was defined as Savary-
`Miller grade 1-2 or Los Angeles grade A-B, whilst severe was con-
`sidered equivalent to Savary-Miller grade 3-5 or Los Angeles grade
`C-D.
`(11) Proportion Helicobacter pylori positive patients included in
`study (if known).
`(12) Patients allowed to have acid suppression or prokinetic ther-
`apy within four weeks of initial endoscopy (permitted versus not
`permitted).
`(13) Symptom severity at entry into the study.
`
`R E S U L T S
`
`Description of studies
`
`See: Characteristics of included studies; Characteristics of excluded
`studies.
`In total, we identified 9360 citations using the search strategy as
`outlined above. In all, 51 papers were included and 129 other trials
`were excluded as they did not meet the eligibility criteria or were
`abstracts of an already included trial. We were unable to extract
`data from a further five trials and correspondence with the authors
`is ongoing (these are all abstracts published between 1982 and
`1997 which have never been published in full). All papers bar one,
`recruited participants from out-patients or open-access endoscopy
`lists. One paper provided data on participants randomised in Asia,
`11 in America/Canada and the rest in Western Europe (including
`one multi-centre study carried out in both Europe and Australia).
`Some of the papers contained more than one comparison and were
`therefore included in more than one analysis as follows:
`For maintenance therapy of oesophagitis
`(1) PPI healing dose versus placebo
`Nine RCTs (Bate 1995 a; Birbara 2000; Caos 2000; Johnson 2001;
`Robinson 1996; Sontag 1996; Sontag 1997; Staerk-Laursen 1995;
`Vakil 2001)
`There were eight multi-centre trials.
`A mean of 254 participants were randomised, the smallest RCT
`included 163 participants (Sontag 1996) and the largest 406 par-
`ticipants (Sontag 1997).
`Data for six trials showed that 690 participants (47%) of those
`randomised had originally had severe oesophagitis (as defined pre-
`viously).
`(2) PPI healing dose versus H2RA
`Ten RCTs (Angelini 1993; Annibale 1998; Dent 1994; Endo
`2000; Gough 1996a; Hallerback 1994; Lundell 1991; Metz 2003;
`Richter 2003; Vigneri 1995)
`
`There were nine multi-centre trials.
`A mean of 258 participants were randomised, the smallest RCT
`included 63 participants (Lundell 1991) and the largest 721 par-
`ticipants (Richter 2003).
`Data for six trials showed that 471 participants (32.1%) of those
`randomised had originally had severe oesophagitis.
`(3) PPI healing dose versus maintenance dose
`Twenty two RCTs (Baldi 1996; Bate 1995 a; Birbara 2000; Caos
`2000; Endo 2000; Escourrou 1999; Gough 1996a; Hallerback
`1994; Hatlebakk 1997b; Jansen 1998; Johnson 2001; Kristensen
`2003; Lauritsen 2003; Metz 2003; Plein 2000; Poynard 1995;
`Richter 2003; Robinson 1996; Sontag 1996; Staerk-Laursen 1995;
`Thjodleifsson 2000; Vakil 2001)
`There were 19 multi-centre trials.
`A mean of 348 participants were randomised, the smallest RCT
`included 97 participants (Endo 2000) and the largest 1224 par-
`ticipants (Lauritsen 2003).
`Data for 13 trials showed that 1527 participants (28.9%) of those
`randomised had originally had severe oesophagitis.
`(4) PPI maintenance dose versus placebo
`Ten RCTs (Bardhan 1998; Bate 1995 a; Birbara 2000; Caos
`2000; Johnson 2001; Pilotto 2003; Robinson 1996; Sontag 1996;
`Staerk-Laursen 1995; Vakil 2001)
`There were nine multi-centre trials.
`A mean of 225 participants were randomised, the smallest RCT
`included 105 participants (Pilotto 2003), the largest 375 partici-
`pants (Vakil 2001).
`Data for seven trials showed that 615 participants (43.3%) of those
`randomised had originally had severe oesophagitis.
`(5)PPI Maintenance dose versus H2RA
`Seven RCTs (Bate 1998; Endo 2000; Festen 1999; Gough 1996a;
`Hallerback 1994; Metz 2003; Richter 2003)
`There were six multi-centre trials.
`A mean of 324 participants were randomised, the smallest RCT
`included 97 participants (Endo 2000), the largest 721 participants
`(Richter 2003)
`Data for four trials showed that 318 participants (24.6%) of those
`randomised had originally had severe oesophagitis.
`(6) H2RA versus placebo
`Five RCTs
`(Armstrong 1989; Hegarty 1997; Kaul 1986;
`Sherbaniuk 1984; Simon 1995)
`There were three multi-centre trials.
`A mean of 148 participants were randomised, the smallest RCT
`included 24 participants (Kaul 1986), the largest 279 participants
`(Hegarty 1997).
`Data for three trials showed that 181 participants (34.5%) of those
`randomised had originally had severe oesophagitis.
`(7) Prokinetics versus placebo
`Six RCTs (Blum 1993; Hatlebakk 1997a; Kimmig 1995;
`McDougall 1997; Toussaint 1991; Tytgat 1992)
`There were five multi-centre trials.
`A mean of 266 participants were randomised, the smallest RCT
`
`Medical treatments for the maintenance therapy of reflux oesophagitis and endoscopic negative reflux disease (Review)
`Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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`included 42 patients (McDougall 1997) and the largest 535 par-
`ticipants (Hatlebakk 1997a).
`Data for all six trials showed that 197 participants (12.4%) of
`those randomised had originally had severe oesophagitis.
`(8) Sucralfate versus placebo
`Two RCTs (Schotborgh 1989; Tytgat 1995 a)
`Both were multi-centre trials.
`Schotborgh 1989 included 26 participants
`Tytgat 1995 a included 184 participants
`Schotborgh 1989 did not present data on oesophagitis severity
`and Tytgat 1995 a did not randomise any patients with severe
`oesophagitis.
`(9) Lansoprazole 15 mg oral doseonce daily (OD) versus 30 mg
`alternate days
`Two RCTs (Baldi 2002; Houcke 2000)
`Both were multi-centre trials
`Houcke 2000 included 52 participants
`Baldi 2002 included 131 participants
`Data for both trials showed that 24 participants (13.3%) of those
`randomised had originally had severe oesophagitis.
`(10) Double dose PPI versus Healing dose PPI
`Two RCTs (Johnson 2001; Vakil 2001)
`Both were multi-centre trials
`Johnson 2001 included 318 participants
`Vakil 2001 included 375 participants
`Vakil 2001 did not present data on oesophagitis severity, for
`Johnson 2001 86 participants (27%) had originally had severe oe-
`sophagitis.
`(11) Healing dose PPI (omeprazole) versus 2nd healing dose PPI
`Two RCTs (Baldi 1996; Carling 1998) compared healing doses of
`omeprazole with lansoprazole and one RCT (Thjodleifsson 2000)
`compared omeprazole with rabeprazole.
`All were multi-centre trials with a mean of 466 participants who
`were randomised. The smallest RCT included 243 participants (
`Thjodleifsson 2000) and the largest 906 participants (Baldi 1996).
`Data for all three trials showed that 425 participants (30.4%) of
`those randomised had originally had severe oesophagitis.
`(12) Maintenance therapy for longer than one year
`One RCT (Thjodleifsson 2003) which was a follow-up to
`Thjodleifsson 2000 with follow-up at three years.
`(13) Other comparisons for oesophagitis maintenance
`In addition, one trial compared treatment with a five different ther-
`apies, including combination treatments (Vigneri 1995). There
`was also one trial which compared two doses of H2RA without
`placebo (Pace 1990).
`For maintenance therapy of ENRD
`The number of studies assessing patients with ENRD was small
`and they examined different drug therapies. These studies have
`therefore been described, rather than formal analysis being carried
`out.
`The three RCTs were:
`Bate 1998, comparing omeprazole 10 mg and cimetidine 800
`
`mg nocte (participants with both oesophagitis (81%) and ENRD
`(19%) but data combined, so presented in the oesophagitis sec-
`tion).
`Hatlebakk 1997a, comparing cisapride and placebo in 535 par-
`ticipants (with both oesophagitis and ENRD, but data presented
`separately) which was a multi-centre trial.
`Venables 1997, comparing omeprazole 10 mg and placebo in 495
`participants which was also a multi-centre trial (ENRD patients
`only).
`
`Risk of bias in included studies
`
`Two reviewers independently undertook an assessment of the
`quality of each eligible study. Methods of randomisation, con-
`cealment, and masking were assessed. Sixteen trials stated the
`method of randomisation (Baldi 2002; Bardhan 1998; Blum
`1993; Carling 1998; Escourrou 1999; Festen 1999; Lundell 1991;
`Plein 2000; Sherbaniuk 1984; Staerk-Laursen 1995; Thjodleifsson
`2000; Thjodleifsson 2003; Toussaint 1991; Tytgat 1992; Vakil
`2001 and Vigneri 1995) and six (Baldi 2002; Bardhan 1998;
`Lauritsen 2003; Metz 2003; Robinson 1996; Vakil 2001) reported
`the method of concealment. All papers from which provided data
`to this review were randomised controlled trials of good quality
`and the majority had similar dropout rates between the 2 compar-
`ative groups.
`
`Effects of interventions
`
`For maintenance therapy of oesophagitis
`(1) PPI healing dose versus placebo
`(a) Maintenance of healed oesophagitis
`Nine RCTs (Bate 1995 a; Birbara 2000; Caos 2000; Johnson 2001;
`Robinson 1996; Sontag 1996; Sontag 1997; Staerk-Laursen 1995;
`Vakil 2001) reported a dichotomous outcome for healing dose of
`PPI versus placebo in the maintenance therapy of oesophagitis;
`evaluating 1385 participants between 26 and 52 weeks. Overall
`21.7% of participants relapsed in the group taking a healing dose
`of PPIs, compared to 78.8% in the placebo group.
`There was statistically significant heterogeneity between the trial
`results (chi squared 37.84, df = 8, p < 0.00001). Meta-regression
`exploring type of PPI, duration of follow-up, age, country, method
`of masking, randomisation and concealment of allocation failed
`to explain this heterogeneity.
`There was a significant benefit of taking healing dose PPI therapy
`compared to placebo to maintain remission of oesophagitis (rela-
`tive risk of relapse (RR) 0.26; 95% confidence interval (CI) 0.19
`to 0.36 with a number needed to treat to gain benefit (NNT) of
`1.7 (95% CI 1.6 to 1.8).
`(b) Maintenance of symptom relief
`Nine RCTs (Bate 1995 a; Birbara 2000; Caos 2000; Johnson 2001;
`Robinson 1996; Sontag 1996; Sontag 1997; Staerk-Laursen 1995;
`
`Medical treatments for the maintenance therapy of reflux oesophagitis and endoscopic negative reflux disease (Review)
`Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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`Vakil 2001) reported a dichotomous outcome for symptom reli