`Ml ORIGINAL CONTRIBUTION JAMA-EXPRESS
`
`Gastrointestinal Toxicity With Celecoxib vs
`Nonsteroidal Anti-inflammatory Drugs
`for Osteoarthritis and Rheumatoid Arthritis
`The CLASS Study: A Randomized Controlled Trial
`
`Context Conventional nonsteroidal anti-inflammatory drugs (NSAIDs) are associ-
`ated with a spectrum of toxic effects, notably gastrointestinal (Gl) effects, because of
`inhibition of cyclooxygenase (COX)-1. Whether COX-2-specific inhibitors are asso-
`ciated with fewerclinical Gl toxic effects is unknown.
`
`
`Fred E. Silverstein, MD
`Gerald Faich, MD
`
`Jay L. Goldstein, MD
`
`Lee S. Simon, MD
`Objective To determine whether celecoxib, a COX-2-specific inhibitor, is associ-
`
`ated with a lower incidence ofsignificant upper G! toxic effects and other adverse ef-
`Theodore Pincus, MD
`fects compared with conventional NSAIDs.
`
`Andrew Whelton, MD
`Design The Celecoxib Long-term Arthritis Safety Study (CLASS), a double-blind, ran-
`
`Robert Makuch, PhD
`domized controlled trial conducted from September 1998 to March 2000.
`
`Glenn Eisen, MD
`Setting Three hundred eighty-six clinical sites in the United States and Canada.
`
`Naurang M. Agrawal, MD
`Participants A total of 8059 patients (=18 years old) with osteoarthritis (OA) or
`rheumatoid arthritis (RA) were enrolled in the study, and 7968received at least 1 dose
`William F. Stenson, MD
`of study drug. A total of 4573 patients (57%) received treatment for 6 months.
`
`Aimee M. Burr, MS
`Interventions Patients were randomlyassigned to receive celecoxib, 400 mg twice
`
`William W. Zhao, PhD
`per day (2 and 4 times the maximum RA and OAdosages, respectively; n=3987);
`ibuprofen, 800 mg 3 times per day (n=1985); or diclofenac, 75 mg twice per day
`Jeflrey D. Kent, MD
`(n=1996). Aspirin use for cardiovascular prophylaxis (=325 mg/d) was permitted.
`
`James B. Lefkowith, MD
`Main Outcome Measures Incidence of prospectively defined symptomatic upper
`
`Kenneth M. Verburg, PhD
`Gl ulcers and ulcer complications (bleeding, perforation, and obstruction) and other
`adverse effects during the 6-month treatment period.
`G. Steven Geis, PhD, MD
`Results Forall patients, the annualized incidence rates of upper GI ulcer complications
`alone and combined with symptomatic ulcers for celecoxib vs NSAIDs were 0.76% vs
`1.45% (P=.09) and 2.08% vs 3.54% (P=.02), respectively. For patients not taking as-
`pirin, the annualized incidence rates of upper Gl ulcer complications alone and combined
`with symptomatic ulcers for celecoxib vs NSAIDs were 0.44% vs 1.27% (P=.04) and
`1.40% vs 2.91% (P=.02). For patients taking aspirin, the annualized incidence rates of
`upperGl ulcer complications alone and combined with symptomatic ulcers for celecoxib
`vs NSAIDs were 2.01 % vs 2.12 % (P=.92) and 4.70% vs 6.00% (P=.49). Fewer celecoxib-
`treated patients than NSAID-treated patients experienced chronic Gl blood loss, Gl in-
`tolerance, hepatotoxicity, or renal toxicity. No difference was notedin the incidence of
`cardiovascular events between celecoxib and NSAIDs,irrespective of aspirin use.
`Conclusions In this study, celecoxib, at dosages greater than those indicated clini-
`cally, was associated with a lowerincidence of symptomatic ulcers and ulcer compli-
`cations combined, as well as other clinically important toxic effects, compared with
`NSAIDsat standard dosages. The decrease in upperGl toxicity was strongest among
`patients not taking aspirin concomitantly.
`
`JAMA, 2000;284:1247-1255 www.jama.com
`Author Affiliations and Financial Disclosuresarelisted
`Lefkowith, MD, Pharmacia Clinical Research and De-
`at the end of this article.
`velopment, 4901 Searle Pkwy, Bldg A3E, Skokie, IL
`60077 (e-mail: James.B.Lefkowith@monsanto.com).
`Corresponding Author and Reprints: James B.
`
`OR PATIENTS WITH MUSCULO-
`
`skeletal disorders, conven-
`tional nonsteroidal anti-
`inflammatory drugs (NSAIDs)
`are a mainstayofclinical care.'? Well-
`established limitations of NSAID
`therapy, however, include the risk of
`developing significant injury to the up-
`per gastrointestinal (GI) tract.*!” The
`annualized incidencerate of symptom-
`atic GL ulcers and ulcer complications
`in NSAID users ranges from 2% to 4%
`(1%-2% for ulcer complications
`alone).!!? NSAID-related ulcer com-
`plications are estimated to lead to
`
`For editorial comment see p 1297.
`
`©2000 American Medical Association. All rights reserved.
`
`(Reprinted) JAMA, September 13, 2000—Vol 284, No, 10 1247
`
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`
`
`GI TOXICITY WITH CELECOXIB VS NSAIDS FOR ARTHRITIS
`
`ing RA or OA evidentfor at least 3
`months and were expected to require
`continuous treatment with an NSAID
`for the duration of the trial. Patients
`were excluded from study participa-
`tion if at screening they had active GI,
`renal, hepatic, or coagulation disor-
`ders; malignancy (unless removed sur-
`gically with no recurrence within 5
`years); esophageal or gastroduodenal
`ulceration within the previous 30 days;
`history of gastric or duodenal surgery
`other than an oversew; or known im-
`mediate-type hypersensitivity to COX-2
`inhibitors, sulfonamides, ibuprofen, or
`diclofenac. Women were excluded if
`they were pregnant, might have be-
`come pregnant, or werelactating.
`
`point evaluation for 2 monthsor until
`studytermination.
`
`Treatment
`
`Patients were randomly assigned to
`receive treatments (celecoxib, 400 mg
`twice perday; ibuprofen, 800 mg 3 times
`perday; or diclofenac, 75 mg twice per
`day) on a 2:1:1 basis by an interactive
`voice response system (ClinPhone, Not-
`tingham, England) according to a com-
`puter-generated randomization sched-
`ule. All treatment regimens were
`blinded and double dummy. Treat-
`ment assignmentfor 3 patients was
`unblinded by study site personnel dur-
`ing trial conduct (1 at the investiga-
`tion site, 2 via the interactive voice
`response system). Noneofthese patients
`experienced astudy outcomeevent. One
`celecoxib patient experienced diver-
`ticular bleeding; 2 patients (1 cele-
`coxib and 1 diclofenac) experienced
`non-Gl-related adverse events; and in
`no instance was the treatmentassign-
`ment made knownto personnelofthe
`drug company (Pharmacia, Skokie,Ill)
`or to members of the oversight com-
`mittees prior to final review of all end
`points by a GI events committee.
`
`Concomitant Medications
`
`NSAIDs(exceptfor stable dosages ofas-
`pirin up to 325 mg/d); antiulcer drugs
`(except for occasional antacid use); an-
`tibiotics used alone or in combination
`with omeprazole, lansoprazole, and ra-
`nitidinefor treatmentof Helicobacter py-
`lori infection; and antineoplastics (ex-
`cept methotrexate or azathioprine for
`RA)were prohibited during the study.
`Use of oral, intramuscular, and intra-
`articular glucocorticoids and disease-
`modifying antirheumatic drugs was per-
`mitted.
`
`Clinical Assessments
`
`Investigators were instructed to iden-
`tify and reportall potential upperGI ul-
`cer complications. Evaluation of such
`events wasoutlined in a prespecified al-
`gorithm structured to reproduceclini-
`cal practice norms. Evaluation was
`required for any ofthe following pre-
`sentations: hematemesis; melena; acute
`
`107000 hospitalizations and 16500
`deaths yearly in the United States.'°
`NSAIDs inhibit cyclooxygenase
`(COX), the enzymeresponsible for con-
`version of arachidonic acid to prosta-
`glandins.'* COX exists in 2 isoforms."
`COX-1 is a ubiquitous constitutive iso-
`zymeproducingprostaglandins respon-
`sible for homeostatic functions such as
`maintenance of GI mucosal integrity.!”
`COX-2is largely a cytokine-inducediso-
`zyme producing prostaglandinsthat me-
`diate pain and inflammation.'’ NSAIDs
`inhibit both COX-1 and COX-2to vary-
`ing degrees.'*” Thus,the therapeutic ef-
`fects of conventional NSAIDsare de-
`rived from inhibition ofCOX-2, while the
`adverse effects of these agents, particu-
`larly in the upper GItract, arise from in-
`hibition of COX-1 activity.
`Celecoxib, a COX-2-specilic inhibi-
`tor, recently was approved by the US
`Food and Drug Administration (FDA)
`for symptomatic treatment of rheuma-
`toid arthritis (RA) and osteoarthritis
`(OA). To determine whether the COX-2
`specificity of celecoxib is associated with
`lower COX-1-related adverseeffects, we
`compared celecoxib administered at
`2 and 4 times the maximum FDA-
`
`approved effective dosages for RA and
`OA,respectively, with commonly used
`therapeutic dosages of ibuprofen and di-
`clofenac. The dosage of celecoxib ex-
`ceeded the maximum dosage approved
`by the FDA for OA and RA to permit a
`safety assessment of the higher dos-
`ages. However, based on previous stud-
`ies,*°?! exceeding the dosages ap-
`proved by the FDA would not improve
`patients’ symptom relief. The dosages of
`ibuprofen anddiclofenac were based on
`prescription data; 48% and 60% of OA
`and RA patients, respectively, who re-
`ceived ibuprofen were prescribed a dos-
`age of at least 2400 mg/d, and 36% and
`57% of OA and RA patients, respec-
`tively, whoreceived diclofenac were pre-
`
`scribed a dosage ofat least 150 mg/d.”
`
`METHODS
`
`Study Protocol
`This prospective, randomized double-
`blind trial was conducted at 386 cen-
`ters in the United States and Canada
`from September 1998 to March 2000
`in accordance with the principles of
`goodclinical practice and the Declara-
`tion of Helsinki. The protocol was ap-
`provedbythe institutional review board
`at eachstudysite, and all patients pro-
`vided written informed consent. Prior
`to enrollment, patients completed a
`physical examination and clinical labo-
`ratory testing. After a baselinevisit, fol-
`low-up clinic visits took place at weeks
`4, 13, and 26 after the initial dose of
`medication, and every 13 weeks there-
`after. All patients were provided an op-
`portunity to complete a minimum of 6
`months of treatment.
`Patients withdrawing from study par-
`ticipation prior to 6 months wereclas-
`sified as follows: preexisting violation
`of entry criteria, protocol noncompli-
`ance (investigator-defined failure to
`comply with the requirements of the
`protocol, eg,failure to take at least 70%
`of the study medication in any 13-
`weekinterval), treatment failure (in-
`vestigator-defined failure of study medi-
`cation to control arthritis signs and
`symptoms), or adverse effect (investi-
`Study Population
`gator-defined signs or symptoms un-
`related to arthritis; see “Clinical As-
`Outpatients aged 18 years or older were
`eligible to participate in the study if, on
`sessments” herein). These patients
`nonetheless were followed up for end-
`screening, they were diagnosed as hav-
`1248 JAMA, September 13, 2000—Vol 284, No, 10 (Reprinted)
`
`©2000 American Medical Association. All rights reserved.
`
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`
`GI TOXICITY WITH CELECOXIB VS NSAIDS FOR ARTHRITIS
`
`Gastric outlet obstruction
`
`Upper gastrointestinal
`bleeding
`
`ewe
`hypovolemia/hypotension; develop-
`Table 1. Protocol-Specified Definitions and Adjudication Criteria for Ulcer Complications
`
`mentof postural dizziness, lighthead-
`Event
`Criteria for Confirmed Event
`edness, or syncope; history of dark
`Gastric or duodenal
`Perforatedlesion requiring surgery. Could involve a laparoscopic
`stool, hematochezia, or anal or rectal
`perforation
`repair, but only if evidence of the perforation was unequivocal,
`such as free air in the abdomen visible on radiograph or
`bleeding; development of new anemia
`peritoneal signs on physical examination.
`(defined as a hematocrit level outside
`Gastric outlet obstruction requiring diagnosis by investigator;
`of the reference range) ora decrease in
`diagnosis was required to be supported by endoscopy (eg,
`ulcer with a tight edernatous pyloric channel) or by
`hematocrit of at least 5 percentage
`radiographic results (eg, dilated stomach, delayed barium
`points; developmentof dyspepsia, ab-
`emptying with clinical evidence of outlet obstruction and with
`
`an ulcer in the channel, severe outlet narrowing and edema)
`dominal pain, or nausea or vomiting;
`Hematemesis with a lesion (ulcer or large erosion) on endoscopy
`or development of occult blood-
`or radiograph
`positive stools. Endoscopy was encour-
`Lesion (ulcer or large erosion) on endoscopy with evidence of
`active bleeding or stigmata of a recent hemorrhage(visible
`aged to documentbleedinglesions but
`vesselor clot attached to the base of an ulcer)
`could also be performedif indicated by
`Melena with a lesion (ulcer or large erosion) on endoscopy or
`radiograph
`the investigator'sclinical judgment.
`Occult blood-positive stool with a lesion (ulcer or large erosion)
`All documentationrelating to poten-
`on endoscopyor radiograph and with evidence of serious
`tial ulcer complications was forwarded
`bleeding, including at least 1 of the following:
`Decrease from baseline in hematocrit of =5 percentage
`to a GI events committee (J.L.G., G.E.,
`points or in hemoglobin of >15 g/L
`N.M.A., and W.F.S). The committee col-
`Posturalvital sign changes (increase in heart rate of
`=20/min and/or decrease in systolic blood pressure
`lectively reviewed each case inatreat-
`of =20 mm Hg and/orin diastolic blood pressure
`ment-blinded fashion and assigned it by
`of =10 mm Hg)
`unanimous consensus as either meet-
`Transfusion of =2 units of blood
`Blood in stomach on endoscopy or nasogastric aspiration
`ing or not meeting the definition of an
`upper GI ulcer complication (TABLE 1).
`Symptomatic ulcers consisted of cases
`that did not meet thedefinition of an ul-
`cer complication but did have endo-
`scopic or x-ray evidenceof a gastric or
`duodenal ulcer as judged by the com-
`mittee. All patients with symptomatic ul-
`cers or ulcer complications were with-
`drawn from the study and included in
`the analysis as having had a study end
`point.
`Adverse effect data werecollected at
`each visit (and as reported spontane-
`ously) using the following question:
`“Since yourlast visit, have you expe-
`rienced or do you currently have any
`symptoms that are not associated with
`your arthritis?” All affirmative re-
`sponses were recordedregardless of se-
`verity or relationship to study drug.
`Laboratory data were also collected at
`eachvisit and as indicated according to
`the investigators’ discretion. Clini-
`cally significant changes in hemato-
`crit and hemoglobin were predefined
`as decreases of at least 10 percentage
`points and 20 g/L, respectively. Clini-
`cally significant changes in serum urea
`nitrogen and creatinine were pre-
`defined as values at 6-month fol-
`low-up of at least 40 mg/dL (14.3
`mmol/L) and 1.8 mg/dL (159 pmol/L),
`
`respectively. Clinically significant
`changes in alanine aminotranslerase
`(ALT)and aspartate aminotransferase
`(AST) were predefined as increases to
`at least 3 times the upperlimit of nor-
`mal. Trial safety (eg, serious adverseel-
`fects) was monitored in a treatment-
`blinded fashion during the study by the
`data safety monitoring board (G-F.,
`T.P., A.W., and R.M.).
`
`in the protocol as consisting of all pa-
`tients whoreceivedat least 1 dose of as-
`signed study medication. An addi-
`tional prespecified analysis was
`performed on the population of pa-
`tients not taking aspirin (since aspirin
`use was a predefined risk factor for GI
`events). Time-to-event analyses of up-
`per GLulcer complications alone or com-
`bined with symptomatic ulcers were per-
`formed based on cumulative eventrates
`Statistical Analysis
`(symptomatic ulcers and/or ulcer com-
`plications) for the 6-month study pe-
`Samplesize calculations were based on
`riod and are expressed as annualized in-
`the assumption that the annualized in-
`cidence rates (numberof events per 100
`cidence of upper GI ulcer complica-
`tions would be 0.3% for celecoxib and
`patient-yearsof exposure or percentage).
`1.2% for NSAIDs. To detect this differ-
`The log-rank test was used to compare
`ence with a 2-sided .05 significancelevel
`time-to-event curves among treatment
`groups. Based on the recommendation
`with statistical power of 85% and as-
`suming a 35% withdrawalrate, a sample
`of the GI events committee and as speci-
`fied by the protocol a priori, upper GI
`size of approximately 4000 patients was
`required for the celecoxib group and
`ulcer complications were defined as a
`study end point (ie, an uncensored
`2000 patients were neededfor each of
`event) if they occurred within the
`the 2 NSAID groups.
`Homogeneityof the treatment groups
`6-month treatment period and oc-
`at baseline was analyzedusingthe y’ test
`curred 48 hours afterthefirst dose day
`or before 14 days after the last known
`for categorical data and 2-way analysis
`ofvariancewith treatment andcenteref-
`dose of study drug (to avoid confound-
`fects for continuous-valueddata. Statis-
`ing dueto prestuclyor poststudy NSAID
`tical analyses were conducted on the in-
`use). Patients who had upper GI ulcer
`complications outside of the specified
`tent-to-treat population,defineda priori
`(Reprinted) JAMA, September 13, 2000—Vol 284, No, 10 1249
`
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`
`GI TOXICITY WITH CELECOXIB VS NSAIDS FOR ARTHRITIS
`
`
`Figure 1. Flowchart of Patient Disposition at
`6 Months
`
`
`9764 Patients Screened
`
`Ciara
`
`
`3987 Received Celecoxib
`3981 Received NSAID
`Treatment
`Treatment
`44 Did Not Receive
`1985 Received
`Celecoxib as
`Ibuprofen
`
`Assigned
`1996 Received
`Diclofenac
`47 Did Not Receive
`
`
`
`
`
`
`
`1611 Withdrawn
`1784 Withdrawn
`732 Adverse Events
`822 Adverse Events
`503 Treatment
`589 Treatment
`Failures
`Failures
`376 Study
`373 Study
`Noncompliance Noncompliance
`
`
`2197 Completed Study
`2376 Completed Study
`
`
`NSAID as Assigned
`
`time frame were censored for purposes
`of time-to-event analysis. This recom-
`mendation was based on the pharma-
`cologic washoutperiod for most com-
`mon NSAIDs and evidence in the
`literature of carryovereffects of NSAIDs
`in terms of GItoxic effects.*Analyses
`were conducted with and without these
`censored patients. The effects of poten-
`tial risk factors for the developmentof
`an ulcer complication (including but not
`limited to concurrent aspirin use) were
`analyzed by Cox proportional hazards
`models. The incidences of treatment-
`emergent adverseeffects or clinical labo-
`ratory changesin the different treat-
`ment groups during the 6 months were
`compared using the Fisher exacttest. All
`P values and 95% confidence intervals
`(CIs) are 2-sided. Nosignificantdiffer-
`ences in adverse events were noted by
`sex, So results are presented with women
`and men combined. Adverse events for
`diclofenac and ibuprofen were similar
`
`except for liver enzyme elevations, for
`whichresults are presented separately.
`RESULTS
`
`A total of 8059 patients were random-
`ized (FIGURE 1), Ninety-one patients
`did not receive study drug (32 were ran-
`domized and foundto be ineligible prior
`to administration of study drug; 59
`withdrew consent priorto taking study
`drug). Of these 91 patients, 44 were ran-
`domized to celecoxib and 47 were ran-
`domized to NSAIDs,
`A total of 7968 patients received at
`least 1 dose of medication. Of these,
`3987 patients were treated with cele-
`coxib, 400 mg twice per day, and 3981
`patients weretreated with NSAIDs (1985
`received ibuprofen, 800 mg3 times per
`day, and 1996 received diclofenac, 75 mg
`twice per day). The celecoxib and NSAID
`groups had 1441 and 1384 totalpatient-
`years of exposure, respectively. Base-
`line characteristics did not differ signifi-
`cantly between groups (TABLE 2). More
`than 20% ofthe patients were taking
`low-dosage aspirin (=325 mg/d). Ap-
`proximately 57% of the patients
`(n=4573) completed 6 monthsoftreat-
`ment (Figure 1). More patients in the
`NSAID treatment group withdrew from
`the study for either adverse effects
`(n=822 [20.6%]) or lack of therapeu-
`tic efficacy (n=589 [14.8%]) than did
`celecoxib-treated patients (n=732
`[18.4%] and n=503 [12.6%], respec-
`tively; P=.01 and P=.005; Figure 1). No
`patients were lost to follow-up (ie, a
`cause of withdrawal was determined for
`all patients who withdrew).
`
`GI Toxicity
`A total of 260 cases were selected by the
`GI events committee for adjudication.
`The committee identified 35 upper GI ul-
`cer complications and another 48 cases
`that represented symptomatic but un-
`complicated gastroduodenal ulcers
`(TABLE 3). Four upper GI ulcer compli-
`cations (2 in celecoxib-treated patients
`and 2 in NSAID-treated patients) were
`censored accordingto predetermined cri-
`teria (see “Methods” section). There-
`maining 177 cases not meeting the defi-
`nition of gastroduodenalulcer or ulcer
`
`Table 2. Baseline Patient Characteristics*
`Celecoxib Group
`NSAID Group
`
`Characteristics
`(n = 3987)
`(n = 3981)
`
`Age, mean(range), y
`60.6 (20-89)
`59.8 (18-90)
`
`>65 y, 9%
`39.1
`37.3
`
`S75 y, %
`12.2
`11.4
`
`Women, %
`68.5
`69.1
`Race/ethnicity, %
`
`White
`88.5
`87.9
`
`Black
`7.5
`8.2
`
`Hispanic
`27
`2.8
`
`Asian
`0.7
`0.8
`
`Other
`0.6
`0.6
`
`Primary rheumatoid arthritis, %
`27.3
`27.5
`Duration of disease, mean (SD), y
`Osteoarthritis
`10.3 (9.7)
`10.1 (9.9)
`
`Rheumatoid arthritis
`11.3,(9.9)
`10.7 (9.6)
`
`NSAID therapy at study entry, %
`81.4
`81.6
`
`Ibuprofen
`21.7
`20.9
`
`Diclofenac
`13.6
`14.0
`Potential risk factor, %
`
`History of gastrointestinal bleeding
`1.7
`1.5
`
`History of gastrointestinal ulcer
`8.4
`8.1
`
`Helicobacter pylori infection, %
`38.5
`38.2
`Tobacco use, %
`15.8
`14.9
`
`Alcohol use, %
`30.9
`30.1
`Concurrent medications, %
`
`Aspirin (3325 mg/d)
`20.9
`20.4
`
`Corticosteroids
`30.6
`29.5
`
`Anticoagulants. 14 1.4
`
`*NSAID indicates nonsteroidal anti-inflammatory drug.
`
`1250 JAMA, September 13, 2000—Vol 284, No, 10 (Reprinted)
`
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`GI TOXICITY WITH CELECOXIB VS NSAIDS FOR ARTHRITIS
`
`1441 patient-years) and 3.68% (51
`events/1384 patient-years) for cele-
`coxib and NSAIDs, respectively
`(P=.03).Corticosteroid use was not sig-
`nificantly associated with the incidence
`of upper GI ulcer complicationsin ei-
`ther treatment group (RR,0.2 and 0.6 for
`patients treated with celecoxib and
`NSAIDs, respectively; P=.13 and P=.27).
`
`group). The annualized incidence of up-
`per GI ulcer complications in non—
`aspirin users wassignificantly lower
`with celecoxib vs NSAIDs (0.44% [5
`events/1143 patient-years] vs 1.27% [14
`events/1101 patient-years]; P=.04; Fig-
`ure 2B). The RR for celecoxib com-
`pared with NSAIDs was 0.35 (95% Cl,
`0.14-0.98). The annualized incidence
`
`SS
`Figure 2. Annualized Incidence of Upper
`Gastrointestinal Tract Ulcer Complications
`Alone and With Symptomatic
`GastroduodenalUlcers
`
`complication were assigned a diagnosis
`from the categories listed in Table 3.
`The annualized incidence ofupper GI
`ulcer complications in celecoxib-
`treated patients was 0.76% (11 events/
`1441 patient-years) vs an incidence of
`1.45% (20 events/1384 patient-years)
`for patients taking NSAIDs (P=.09;
`FIGURE 2A). The relative risk (RR) for
`celecoxib compared with NSAIDs was
`GI Toxicity With Aspirin Use
`0.53 (95% CI, 0.26-1.11). The annu-
`alized incidence of upper GI ulcer com-
`Based on time-to-event analyses using
`a Cox proportional hazard model, low-
`plications plus symptomatic ulcers with
`celecoxib was 2.08% (30 events/1441
`dosage aspirin use was found to have a
`significanteffect on the incidence of up-
`patient-years) vs 3.54% (49 events/
`1384 patient-years) for patients tak-
`per GI ulcer complications in celecoxib-
`treated patients. Within the celecoxib
`ing NSAIDs (P=.02; Figure 2A). The RR
`treatment group, the RR of an upper GI
`for celecoxib compared with NSAIDs
`was 0.59 (95% CI, 0.38-0.94).
`ulcer complication was 4.5 with low-
`Inclusion of the 2 censored events in
`dosage aspirin use: 6 events in 833 pa-
`tients taking low-dosage aspirin vs 5
`each groupdid not alter the interpreta-
`tion of results. For upper GI ulcer com-
`events in 3154 non—aspirin users
`(P=.01). Low-dosageaspirin use did not
`plications, the rates without censoring
`have a significanteffect on therate ofup-
`were 0.90% (13 events/1441 patient-
`per GI ulcer complications in patients
`years) and 1.59% (22 events/1384 pa-
`receiving NSAIDs (RR, 1.7; P=.29).
`tient-years) for celecoxib and NSAIDs,
`When the non-aspirin-using co-
`respectively (P=.11). For upper GI ul-
`cer complications plus symptomatic ul-
`hort was examined, 2 upper GI ulcer
`|B|Patients Not Taking Aspirin
`cers, the rates were 2.22% (32 events/
`complications were censored (1 in each
`
`B Celecoxib
`B NSAIDs
`
`P=.02
`49/1384
`
`.
`A| All Patients
`
`6 5
`
`4
`
`&
`fy5
`Do
`£3
`2
`2
`82&
`=
`
`1
`
`0
`
`P=.08
`20/1384
`
`14/1441 [|
`
`
`
`30/1441
`
`
`
`Pato
`-———
`32/1101
`
`P=.04
`
`44/1101
`
`16/1143
`
`
`
`f
`
`
`5/1143
`
`
`
`
`
`pase
`—
`
`able 3. Adjudicated Cases Meeting and Not Meeting Prespecialized Definitions of
`Gastroduodenal Ulcers and Ulcer Complications*
`Celecoxib Group
`NSAID Group
`
`(n = 3987)
`(n = 3981)
`
`Total No. of cases adjudicated
`444
`149T
`No.of adjudicated cases not meeting the definition
`of a gastroduodenalulcer or ulcer complication
`Esophageal disease
`23
`21
`
`Gastroduodenitis
`12
`21
`
`
`Colonic or small bowel disease
`10
`7
`
`G] Patients Taking Aspirin=P=49
`
`
`Nonulcer bleeding
`10
`17
`6
`17/283
`Miscellaneous Gl symptoms
`18
`20
`Anemia
`5
`12
`
`Cholelithiasis
`1
`0
`
`Total
`79
`98
`No.of adjudicated cases meeting the definition
`of a gastroduodenal ulcer or ulcer complication
`
`Gastroduodenal ulcers
`19
`29
`
`Ulcer complicationst
`13
`22
`
`Upper Gl bleeding
`10
`20
`Perforation
`O
`0
`
`Gastric outlet obstruction
`1
`0
`
`Total 51 32
`
`*NSAID indicates nonsteroidal anti-inflammatory drug; Gl, gastrointestinal.
`Numbers above bars indicate events per patient-
`+P<.001 vs celecoxib group.
`tFour ulcer complications (2 in the celecoxib group and 2 in the NSAID group) were censored from the analysis be-
`years of exposure. NSAIDsindicates nonsteroidalanti-
`cause of the timing of the event based on a priori-specified definitions.
`inflammatory drugs.
`
`# 5
`8
`5 4
`3 3
`3
`an
`9
`8
`Cc
`<
`
`1 |
`0
`
`2 5
`4
`
`oe
`
`a T
`
`é
`g 3
`3
`aCc
`2
`&
`a1
`0
`
`
`
`6/283
`
`14/298
`
`
`
`e293
`
`
`
`
`
`Ulcer Complications
`Symptomatic
`Ulcers and
`Ulcer Complications
`
`©2000 American Medical Association. All rights reserved.
`
`(Reprinted) JAMA, September 13, 2000—Vol 284, No, 10 1251
`
`Downloaded From:http://jama,jamanetwork.com/ by a Reprints Desk User on 03/20/2015
`Page 5 of 9
`
`Patent Owner Ex. 2044
`Mylan v. Pozen
`IPR2017-01995
`
`Page 5 of 9
`
`Patent Owner Ex. 2044
`Mylan v. Pozen
`IPR2017-01995
`
`

`

`
`GI TOXICITY WITH CELECOXIB VS NSAIDS FOR ARTHRITIS
`
`For patients taking aspirin (Figure
`2C), the annualized incidences of symp-
`tomatic ulcers and/or upper GI compli-
`cations were not significantly different
`in patients taking celecoxib vs NSAIDs.
`For upper GI complications, the ob-
`served rates were 2.01% for patients tak-
`ing celecoxib vs 2.12% for patients tak-
`ing NSAIDs (6 events/298 patient-
`years vs 6 events/283 patient-years,
`respectively; P=.92). For upper GI ul-
`cer complications plus symptomatic ul-
`cers, the observed rates were 4.70% for
`patients taking celecoxib vs 6.00% for
`patients taking NSAIDs (14 events/298
`patient-years vs 17 events/283 patient-
`years, respectively; P=.49). Including the
`2 censored events (1 in each group), the
`rates were 2.35% and 2.47%, respec-
`tively, for upper GI ulcer complica-
`tions and 5.03% and 6.36%, respec-
`tively, for upper GI ulcer complications
`plus symptomatic ulcers.
`
`of upper GI ulcer complications plus
`symptomaticulcers in patients not tak-
`ing aspirin wasalso significantly lower
`with celecoxib than with NSAIDs
`(1.40% [16 events/1143 patient-
`years] vs 2.91% [32 events/1101 pa-
`tient-years]; P=.02; Figure 2B). The RR
`for celecoxib compared with NSAIDs
`was 0.48 (95% CI, 0.28-0.89).
`Inclusion of the 1 censored event in
`each groupdid notalter the interpreta-
`
`tion of results. For upper GI ulcer com-
`plications, the rates without censoring
`were 0.52% (6 events/1143 patient-
`years) and 1.36% (15 events/1101 pa-
`tient-years) for celecoxib and NSAIDs,
`respectively (P=.05). For upper GI ul-
`cer complications plus symptomatic ul-
`cers, the rates were 1.49% (17 events/
`1143 patient-years) and 3.00% (33
`events/1101 patient-years) forcele-
`coxib and NSAIDs,respectively (P=.02).
`
`a T
`
`able 4. Adverse Effects During the 6-Month Treatment Period"
`All Patients
`Patients Not Taking Aspirin
`elecoxib Group NSAID Group Celecoxib Group NSAID Group
`Adverse Effects
`(n = 3987)
`(n = 3981)
`(n = 3154)
`(n = 3169)
`Gastrointestinal
`
`Dyspepsia
`575 (14.4)
`640 (16.1)t
`427 (13.5)
`496 (15.7)
`
`Abdominal pain
`387(9.7)
`522 (13.1)t
`286 (8.1)
`395 (12.5)t
`
`Diarrhea
`373 (9.4)
`392 (9.8)
`288 (9.1)
`293 (9.2)
`
`Nausea
`277 (6.9)
`370 (9.3)t
`213 (6.8)
`277 (8.7)F
`
`Constipation
`68 (1.7)
`234 (6.9)t
`48 (1.5)
`172 (6.4)
`
`Total
`1250 (31.4)
` 1465(96.8)t
`942 (29.9)
`1127 (85.6)t
`
`Withdrawals
`345(8.7)
`427 (10.7)t
`252(8.0)
`321 (10.1)t Other Adverse Effects
`Hepaticad serurn ALT
`2308
`B32
`1806
`63 2.1
`Adverse effects with an incidenceof at
`
`
`Slevated serum AST
`18 (0.5)
`73 (1.8}t
`13 (0.4)
`60 (1.9)t
`least 5% in either treatment group dur-
`
`Total
`24 (08)
`93 @.3)t
`18 (08)
`72 (23yt
`ing the 6-month treatmentperiod were
`
`Withdrawals
`2 (<0.1)
`46 (1,2)
`2 (<0.1)
`36(1.1)+
`1 Symptoms, upperrespiratory tract
`Bieeding-related
`infection or related symptoms, head-
`
`Anemia
`81 (2.0)
`175 (4.4)t
`59 (1.9)
`123 (3.9)t
`ache, and rash. Adverse effects caus-
`
`Ecchymosis
`28 (0.7)
`32 (0.8)
`22(0.7)
`26 (0.8)
`ing withdrawal with an incidenceof at
`Hematochezia
`17 (0.4)
`40 (1.0}t
`11 (0.3)
`29 (0.9)+
`least 1% in either treatment group were
`
`Total
`123 (3.1)
`238 (6.0}t
`90 (2.9)
`171 (5.4)t
`Gl symptoms, rash, and elevated trans-
`
`Withdrawals
`16 (0.4)
`26 (0.7)
`13 (0.4)
`19 (0.6)
`aminaselevels. For these categories, ce-
`Renal
`lecoxib was associated with equiva-
`
`Peripheral edema
`113 2.8)
`138 (8.5)
`90 (2.9)
`108 (8.4)
`lent or lower incidences of adverse
`
`Hypertension
`66 (1.7)
`90 (2.3)t
`50 (1.6)
`65 (2.1)
`effects and withdrawals compared with
`
`— creatinine level
`28 (0.7)
`46 (1.2)
`20 (0.6)
`33 (1.0)
`NSAIDtherapy, with the exceptions of
`
`ie
`200 (6.0)
`263 (6.6)t
`155 (4.9)
`198 (6.2)
`rash and pruritus (TABLE 4).
`
`withdrawals
`44 (1-1)
`41 (1-0)
`37 (1.2)
`$2 (1.0)
`Serious adverseeffects (representing
`
`oeerebrovasculer accident 5(0.2)__hospitalizations or malignancies de-5 (0.1) 100.3) 3 (<0.1)
`
`
`
`
`
`
`Myocardial infarction 4(0.1)___tected during the 6-monthtreatmentpe-10 (0.3) 110.3) 3 (<0.1)
`
`
`
`
`Angina
`24 (0.6)
`22 (0.6)
`10 (0.3)
`7 (0.2)
`riod) were reported for 4.3% of cele-
`Total
`37 (0.9)
`39(1.0)
`16 (0.5)
`14 (0.4)
`coxib patients (172 events/3987
`
`Withdrawals
`12 (0.3)
`13 (0.3)
`9 (0.3)
`5 (0.2)
`patients) and 4.2% of NSAID patients
`Cutaneous
`(168 events/3981 patients). The most
`Rash
`218 (6.5)
`103 (2.6)t
`180 (5.7)
`91 (2.9)
`commonserious adverseeffects in pa-
`
`Pruritus
`91 (2.3)
`59 (1.5)t
`72(2.8)
`44(14)F
`tients taking celecoxib and NSAIDs were
`
`Urticaria
`22(0.6)
`14 (0.4)
`18 (0.6)
`13 (0.4)
`accidental fractures (7 and 8 events, re-
`
`Total
`298 (7.5)
`163 (4.1)t
`241 (7.6)
`136 (4.3)
`spectively), back pain (8 and 8 events,
`Withdrawals
`109 (2.7)
`49 (1.2)t
`92 (2.9)
`43 (1.4)t
`respectively), pneumonia (9 and 9
`“Data are given as No.(%) of patients. Categories are nonadditive; patients may have experienced more than 1 ad-
`verse event in each category. NSAID indicates nonsteroidal anti-inflammatory drug; ALT, alanine aminotransferase;
`events, respectively), cardiac failure (9
`and AST, aspartate aminotransferase.
`and 10 events, respectively), myocar-
`tPs.05 vs celecoxib group.
`dial infarction (10 and 10 events, re-
`
`aC
`
`1252 JAMA, September 13, 2000—Vol 284, No, 10 (Reprinted)
`
`©2000 American Medical Association. All rights reserved.
`
`Downloaded From:http://jama,jamanetwork.com/ by a Reprints Desk User on 03/20/2015
`Page 6 of 9
`
`Patent Owner Ex. 2044
`Mylan v. Pozen
`IPR2017-01995
`
`Page 6 of 9
`
`Patent Owner Ex. 2044
`Mylan v. Pozen
`IPR2017-01995
`
`

`

`
`GI TOXICITY WITH CELECOXIB VS NSAIDS FOR ARTHRITIS
`
`SS
`Figure 3. Patients With Decreases in
`Hematocrit and/or Hemoglobin at 6 Months
`
`@ Celecoxib
`
`
`@ NSAIDs
`
`P<,001
`
`4.0
`35
`3.0
`
`135/3651
`
`Pe.001
`1
`107/3487
`
`oOOo
`R 25
`§ 2.03
`£15
`1.0
`05
`
`|
`0
`All Patients
`Patients Without
`Gl Disease
`
`
`58/3701
`
`
`
`
`
`50/3582
`
`
`
`Data are shownfor patients with decreases from pre-
`treatmentlevels in hematocrit of 10 percentage points
`or more, in hemoglobin of 20 g/L or more, or both.
`Results for the entire study population are shown on
`the left. On theright, results for all patients exclud-
`ing those with an upper gastrointestinal (GI) ulcer com-
`plication, symptomatic ulcer, or other diagnosed Gl
`disease are show