`- ORIGINAL CON'i‘RlBtJ'I‘ION JAMAu EXPRESS
`
`Gastrointestinal Toxicity With Celecoxib vs
`Nonsteroidal Anti-inflammatory Drugs
`for Osteoarthritis and Rheumatoid Arthritis
`
`Context Conventional nonsteroidal anti-inflammatory drugs (NSAle) are associ-
`ated with a spectrum of toxic effects, notably gastrointestinal (GI) effects, because of
`inhibition of cyclooxygenase (COX)-1. Whether COX-2—specific inhibitors are asso-
`ciated with fewer clinical GI toxic effects is unknown.
`
`Objective To determine whether celecoxib. a COX-Z-specific inhibitor, is associ-
`ated with a lower incidence of significant upper GI toxic effects and other adverse ef-
`fects com pared with conventional NSAIDs.
`
`Design The Celecoxib Long-term Arthritis Safety Study (CLASS), a double-blind, ran-
`domized controlled trial conducted from September 1998 to March 2000.
`Setting Three hundred eighty-six clinical sites in the United States and Canada.
`
`The CLASS Study: A Randomized Controlled Trial
`
`Fred E. Silverstein, MD
`Gerald Faich, MD
`
`.Iay L. Coldstein. Ml)
`
`Lee 5. Simon, MD
`
`rl‘heodore Pincus, MI)
`
`Andrew Whellon, MD
`
`Robert Maktudt, I’hl)
`
`Glenn Risen, MD
`
`Naurang M. Agrawal, MI)
`Participants A total of 8059 patients (218 years old) with osteoarthritis (CA) or
`rheumatoid arthritis (RA) were enrolled in the study. and 7968 received at least 1 close
`William F. Slenson, MD
`of study drug. A total of 4573 patients (57%] received treatment for 6 months.
`
`Aimee N1. Burr, MS
`Interventions Patients were randomly assigned to receive celecoxib. 400 mg twice
`
`William W. Zhao, PhD
`per clay {2 and 4 times the maximum RA and 0A dosages. respectively; n=3987);
`ibuprofen. 800 mg 3 times per day (n=1985); or diclofenac. 75 mg twice per day
`Jeffrey D. Kent, M l)
`(n_1996). Aspirin use for cardiovascular prophylaxis (E325 mg/d} was perm itted.
`
`James B. Lefkowith, MD
`Main Outcome Measures Incidence of prospectively defined symptomatic upper
`
`Kenneth M. Verlturg, Phl)
`GI ulcers and ulcer complications (bleeding. perforation, and obstruction) and other
`adverse effects during the 6—month treatment period.
`C. Steven Geis, l’hl), Ml)
`Results For all 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 an nuaJized incidence rates of u pper GI ulcer complications alone and combined
`with symptomatic ulcers for celecoxib vs NSAIDs were 0.44% vs 1.27% (P=.04) and
`1 110% vs 2.91% (P202). For patients taking aspirin, the annualized incidence rates of
`upper GI ulcer complications alone and combined with symptomatic ulcers for celecoxib
`vs NSAIDs were 2.01 % v52.‘] 2% (P: .92) and 4.70% vs 6.00% (P: .49). Fewer celecoxib-
`treated patients than NSAlD-treated patients experienced chronic GI blood loss, CI in-
`tolerance, hepatotoxicity. or renal toxicity. No difference was noted in 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 lower incidence of symptomatic ulcers and ulcer compli-
`cations combined. as well as other clinically important toxic effects. compared with
`NSAIDs at standard dosages. The decrease in upper GI toxicity was strongest among
`patients not taking aspirin concomitantly.
`
`JAMA. 2000;284:1247-1255 www.jama.com
`Author Affiliations and Financial Disclosutes are listed
`Lefkowithy MD, Pharmacla Clinical Research and De-
`at the end of this article.
`velopment. 4901 Searle Pkwy. Bldg ABE, Skokie. IL
`600?? (email: iames.B.Lefkowith®monsanto.com).
`Corresponding Author and Reprints: James B.
`
`on PATIENTS WITH MUSCULOV
`
`skeletal disorders, conven-
`tional nonsteroidal anti-
`
`inflammatory drugs (NSAIDs)
`are a mainstay ofclinical care.” Well-
`established limitations of NSAID
`
`therapy, however, include the risk of
`developing significant injury to the up—
`per gastrointestinal (GI) tract.“" The
`annualized incidence rate of symptom-
`atic GI ulcers and ulcer complications
`in NSAID users ranges from 2% to 4%
`(1%-2% for ulcer complications
`alone).”'1'5 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. Scplt‘mln‘r 13. ZOOO—V‘nl 28+. No. 10 1247
`
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`
`GI TOXICITY WITH CELECOXIB VS NSAIDS FOR ARTHRITIS
`
`ing RA or CA evident for 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 ifat 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 were lactating.
`
`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
`good clinical practice and the Declara—
`tion of Helsinki. The protocol was ap-
`proved by the institutional review board
`at each study site, and all patients pre—
`vided written informed consent. Prior
`
`to enrollment, patients completed a
`physical examination and clinical labo-
`ratory testing. After a baseline visit, 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.
`
`point evaluation for 2 months or until
`study termination.
`
`Treatment
`
`Patients were randomly assigned to
`receive treatments (celecoxib, 400 mg
`twice per day; ibuprofen, 800 mg 3 times
`per day; 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 assignment for 3 patients was
`unblinded by study site personnel durr
`ing trial conduct (1 at the investiga—
`tion site, 2 via the interactive voice
`response system). None of these patients
`experienced a study outcome event. One
`celecoxib patient experienced diverr
`ticular bleeding; 2 patients (1 cele—
`coxib and 1 diclofenac) experienced
`non—Gl-related adverse events; and in
`no instance was the treatment assign-
`ment made known to personnel of the
`drug company (Pharmacia, Skokie, III)
`or to members of the oversight comr
`mittees prior to final review of all end
`points by a GI events committee.
`
`Concomitant Medications
`
`NSAIDs (except for stable dosages of as-
`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-
`nitidine for treatment of Helicobacterpy—
`fort 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-
`modifyingantirheumatic drugs was per-
`mitted.
`
`Clinical Assessments
`
`Investigators were instructed to iden-
`tify and report all potential upper GI ul—
`cer complications. Evaluation of such
`events was outlined in a prespecified alr
`gorithm structured to reproduce clini—
`cal practice norms. Evaluation was
`required for any of the following pre—
`sentations: hematemesis; melena; acute
`
`107 000 hospitalizations and 16 500
`deaths yearly in the United States.10
`NSAIDs inhibit cyclooxygenase
`(COX), the enzyme responsible for con—
`version of arachidonic acid to prosta-
`glandins.” COX exists in 2 isoforms.”
`COX-1 is a ubiquitous constitutive iso-
`zyme producing prostaglandins respon-
`sible for homeostatic functions such as
`
`maintenance of GI mucosal integrity.”
`COX—2 is largely a cytokine—induced iso—
`zyrne producing prostaglandins that me—
`diate pain and inflammation.” NSAIDs
`inhibit both COX-1 and COX-2 to vary-
`ing degrees."”° Thus, the therapeutic ef-
`fects of conventional NSAIDs are de
`rived from inhibition ofCOX—2, while the
`adverse effects of these agents, particu-
`larly in the upper GI tract, arise from in-
`hibition ofCOX—l activity.
`Celecoxib, a COX727specific inhibir
`tor, recently was approved by the US
`Food and Drug Administration (FDA)
`for symptomatic treatment of rheuma-
`toid arthritis (RA) and osteoarthritis
`(0A), To determine whether the COX—2
`specificity of celecoxib is associated with
`lower COXrlirelated adverse effects, we
`compared ceIecoxib administered at
`2 and 4 times the maximum FDA-
`
`approved effective dosages for RA and
`0A, 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 CA and RA to permit a
`safety assessment of the higher dos-
`ages. However. based on previous stud—
`iesf‘m' exceeding the dosages ap-
`proved by the FDA would not improve
`patients’ symptom relief. The dosages of
`ibuprofen and diclofenac were based on
`prescription data; 48% and 60% of OA
`and RA patients, respectively, who re-
`ceived ibuprofen were prescribed a dose
`age of at least 2400 mg/d, and 36% and
`57% of 0A and RA patients, respec-
`tively, who received diclofenac were pre-
`
`scribed a dosage of at least 150 mgfd.”
`
`METHODS
`
`Patients withdrawing from study par—
`ticipation prior to 6 months were clas-
`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-
`week interval), treatment failure (in-
`vestigator-defined failure of study medi—
`cation to control arthritis signs and
`symptoms), or adverse effect (investir
`Study Population
`gator—defined signs or symptoms un—
`related to arthritis; see “Clinical As-
`Outpatients aged 18 years or older were
`sessments" herein}, These patients
`eligible to participate in the study if, on
`screening, they were diagnosed as hav—
`nonetheless were followed up for end—
`1263 JAMA. St‘plt‘mbcr l 3, ZOOO—vVol 284, No 10 (Reprinted)
`
`©2000 American Medical Association. All rights reserved.
`
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`
`GI TOXICITY WITH CELECOXIB VS NSAIDS FOR ARTHRITiS
`
`— T
`
`Gastric outlet obstruction
`
`Upper gastrointestinal
`bleeding
`
`able 1. Protocol-Specified Definitions and Adjudication Criteria for Ulcer Complications
`
`Event
`Criteria for Continued Event
`Gastric or duodenal
`Perforated lesion requiring surgery. Gould involve a laparoscopic
`perforation
`repair, but only if evidence of the pedoration was unequivocal,
`such as free air in the abdomen Visible on radiograph or
`peritoneal signs on physical examination.
`Gastric outlet obstruction requiring diagnosis by investigator;
`diagnosis was required to be supported by endoscoliilr {99‘
`ulcer with a tight edematous pyloric channel) or by
`radiographic results leg. dilated stomach, delayed barium
`emptying with clinical evidence of outlet obstruction and with
`
`an ulcer in the channel. severe outlet narrowing and edema)
`Hematemesis with a lesion (ulcer or large erosion) on endoscopy
`or radiograph
`Lesion (ulcer or large erosion) on endoscopy with evidence of
`active bleeding or Stigmata ot a recent hemorrhage (visible
`vessel or clot attached to the base oi an ulcer)
`Malena with a lesion (ulcer or large erosion) on endoscopy or
`radiograph
`Occult blood-positive stool with a lesion (ulcer or large erosion)
`on endoscopy or radiograph and with evidence of serious
`bleeding, including at least 1 of the following:
`Decrease from baseline in hematocrit of 25 percentage
`points or in hemoglobin of >15 gfL
`Postural vital sign changes (increase in heart rate of
`zzofmin andfor decrease in systolic blood pressure
`of 220 mm Hg andr‘or in diastolic blood pressure
`of 210 mm Hg}
`Transfusion of 22 units of blood
`Blood in stomach on endoscopy or nasogastiic aspiration
`
`respectively. Clinically significant
`changes in alanine aminotransferase
`(ALT) and aspartate aminotransferase
`(AST) were predefined as increases to
`at least 3 times the upper limit of nor-
`mal. Trial safety (eg, serious adverse ef-
`fects) was monitored in a treatment-
`blinded fashion during the study by the
`data safety monitoring board (G.F.,
`T.P., A.W., and RM.)
`
`in the protocol as consisting of all pa-
`tients who received at 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 Gl ulcer complications alone or com-
`bined with symptomatic ulcers were per-
`formed based on cumulative event rates
`
`Statistical Analysis
`Sample size calculations were based on
`the assumption that the annualized in-
`cidence of upper GI ulcer complica-
`tions would be 0.3% for celecoxib and
`1.2% for NSAle. To detect this differ-
`
`ence with a Z-sided .05 significance level
`with statistical power of 85% and as-
`suming a 35% withdrawal rate, a sample
`size ofapproximately 4000 patients was
`required for the celecoxib group and
`2000 patients were needed for each of
`the 2 NSAID groups.
`Homogeneity of the treatment groups
`at baseline was analyzed using the )6 test
`for categorical data and Z—way analysis
`ofvariance with treatmentand center ef.
`fects for continuous-valued data. Statis-
`
`(symptomatic ulcers andlor ulcer com—
`plications) for the 6-month study pe—
`riod and are expressed as annualized in~
`cidence rates (number of events per 100
`patient-years of exposure or percentage).
`The log-rank test was used to compare
`time-to-event curves among treatment
`groups. Based on the recommendation
`of the GI events committee and as speci-
`fied by the protocol a priori, upper GI
`ulcer complications were defined as a
`study end point (ie, an uncensored
`event) if they occurred within the
`6—month treatment period and oc-
`curred 48 hours after the first dose day
`or before 14 days after the last known
`dose of study drug (to avoid confound—
`ing due to prestudy or poststudy NSAID
`use). Patients who had upper GI ulcer
`tical analyses were conducted on the in—
`complications outside of the specified
`tent—to—treat population, defined a priori
`(Reprinted) .IAMA. September l3. ZOOO—Nul 284. No. l0 1249
`
`hypovolemia/hypotension; develop-
`ment of postural dizziness, lighthead-
`edness, or syncope; history of dark
`stool, hematochezia. or anal or rectal
`bleeding; development of new anemia
`(defined as a hematocrit level outside
`of the reference range) or a decrease in
`hematocrit of at least 5 percentage
`points; development of dyspepsia, ab-
`dominal pain. or nausea or vomiting;
`or development of occult blood—
`positive stools. Endoscopy was encour—
`aged to document bleeding lesions but
`could also be performed if indicated by
`the investigator’s clinical judgment.
`All documentation relating to potenr
`tial ulcer complications was forwarded
`to a GI events committee (j.L.G., G.E.,
`N.M.A., and WES). The committee col-
`lectively reviewed each case in a treat—
`ment—blinded fashion and assigned it by
`unanimous consensus as either meet—
`
`ing or not meeting the definition of an
`upper GI ulcer complication (TABLE 1).
`Symptomatic ulcers consisted of cases
`that did not meet the definition of an ul—
`
`cer complication but did have endo-
`scopic or xrray evidence of 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 were collected at
`
`each visit (and as reported spontane—
`ously) using the following question:
`“Since your last visit, have you expe—
`rienced or do you currently have any
`symptoms that are not associated with
`your arthritis?" All affirmative re-
`sponses were recorded regardless of se-
`verity or relationship to study drug.
`Laboratory data were also collected at
`each visit 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-
`
`lowrup of at least 40 mg/dl. (14.3
`mmol/L) and 1.8 mg/dL (159 pmol/L),
`
`©2000 American Medical Association. All rights reserved.
`
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`

`
`GI TOXICITY WITH CELECOXIB VS NSAIDS FOR ARTHRITIS
`
`
`Figure 1 . Flowchart of Patient Disposition at
`6 Months
`
`
`9764 Patieils Sweened
`
`
`
`
`
`8997 Received Celeooxib
`3991 Fiecenred NSAID
`Treatment
`Treatment
`44 Did Not Receive
`1985 Received
`Celeooxib as
`Ibuprofen
`
`Assigned
`1996 Received
`Diciotenac
`47 Did Not Receive
`
`NSAID as Assigied
`
`
`
`1?84 Withdrawn
`1611 Withdrawn
`822 AMSB Events
`732 more Events
`508 Tmatmenl
`589 Treatment
`Failures
`Falures
`376 Study
`373 Study
`
`Nomiiiance Noncon'diame
`
`
`
`
`
`
`
`
`219'.r Completed $11.10*,l
`2376 Completeds‘ltm
`
`
`time frame were censored for purposes
`of time-to-event analysis. This recom-
`mendation was based on the pharma—
`cologic washout period for most com—
`mon NSAIDs and evidence in the
`
`literature of carryover effects ofNSAIDs
`in terms of GI toxic effects.3sz Analyses
`were conducted with and without these
`
`censored patients. The effects ofpoten-
`tial risk factors for the development of
`an ulcer complication [including but not
`limited to concurrent aspirin use) were
`analyzed by Cox proportional hazards
`models. The incidences of treatment—
`
`emergent adverse effects or clinical labo-
`ratory changes in the different treatr
`ment groups during the 6 months were
`compared using the Fisher exact test. All
`P values and 95% confidence intervals
`
`(C15) are Z—sided. No significant differ—
`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
`which results 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 found to be ineligible prior
`to administration of study drug; 59
`withdrew consent prior to taking study
`drug). Ofthese 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 celer
`coxib, 400 mg twice per day, and 3981
`patients were treated with NSAIDs (1985
`received ibuprofen1 800 mg 3 times per
`day. and 1996 received diclofenac, 75 mg
`twice per day). The celecoxib and NSAID
`groups had 1441 and 1384 total patient—
`years of exposure. respectively. Base—
`line characteristics did not differsignifi-
`cantly between groups (TABLE 2). More
`than 20% of the patients were taking
`low-dosage aspirin (S325 mg/d). Ap-
`proximately 57% of the patients
`(n:4573) completed 6 months oftreat—
`merit (Figure I). More patients in the
`NSAID treatment group withdrew from
`the study for either adverse effects
`(n:822 [20636]) or lack of therapeu-
`tic efficacy (n=589 [14.8%]) than did
`celecoxib—lrealed patients (n: 732
`[18.4%] and n:503 [12.6%], respec—
`tively; P: .01 and P: .005; Figure I). No
`patients were lost to follow—up (ie, a
`cause ofwithdrawal was determined for
`
`all patients who withdrew).
`
`GI Toxicity
`A total of260 cases were selected by the
`GI events committee for adjudication.
`The committee identified 35 upper (31 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-Lreated patients
`and 2 in NSAIDrtreated patients) were
`censored according to predetermined cri—
`teria (see "Methods“ section). The re-
`maining 177 cases not meeting the deli—
`nition of gastroduodenal ulcer or ulcer
`
`Table 2. Baseline Patient Characteristics“
`Celecoxib Group
`NSMD Group
`
`Characteristics
`(n = 398?]
`(n = 3981}
`
`Age, mean (range). 3*
`60.6 (20-89]
`59.8 (18-90)
`
`>65 y. %
`39.1
`37.3
`
`>75 y, ‘36
`12.2
`11.4
`
`Women. 96
`68.5
`69.1
`Racefethnicity, 91:
`
`White
`88.5
`87.9
`
`Black
`7.5
`8.2
`
`Hispanic
`2.7
`2.8
`
`ASian
`0.7
`0.8
`
`Other
`0.5
`0.5
`
`Primary rheumatOId arthritis, 96
`27.3
`2?.5
`Duration of disease, mean (30), y
`Osteoarthritis
`10.3 (9.7)
`10.1 (9.9)
`
`Rheumatoid arthritis
`11.3 (9.9)
`10.? (9.6)
`
`NSAID therapy at study entry, %
`81.4
`31.6
`
`Ibuproten
`21.7r
`20.9
`
`Diclotenac
`13.5
`14.0
`Potential risk factor, ‘36
`
`History of gastrointestinal bleeding
`1.?
`1.5
`
`History of gastrointestinal ulcer
`8.4
`8.1
`
`Helicobacrer pylori infection. 96
`38.5
`38.2
`Tobacco use. %
`15.8
`14.9
`
`Alcohol use. ‘18
`30.9
`30.1
`Concurrent medications. %
`
`Aspirin [1:325 mg/d)
`20.9
`20.4
`
`Corticosteroids
`30.6
`29.5
`Anticoagulants t .1 1.1
`
`
`*NSND indicates noristeroidal antieim'lamrmtory drug.
`
`1250 JAMA. September I 3, 2000—th1] 284, No 10 (Reprinted)
`
`©2000 American Medical Association. All rights reserved.
`
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`

`
`GI TOXICITY WITH CELECOXIB VS NSAIDS FOR ARTHRITIS
`
`group). The annualized incidence of up-
`per GI ulcer complications in non—
`aspirin users was significantly lower
`with celecoxib vs NSAIDs (0.44% [5
`events/1143 patient-years] vs 1.27% [14
`eventsll 101 patient—years]; P=.04;1'-ig—
`ure 2B). The RR for celecoxib com-
`pared with NSAIDs was 0.35 (95% CI,
`0.14-0.98). The annualized incidence
`
`— F
`
`igure 2. Annualized Incidence of Upper
`Gastrointestinal Tract Ulcer Complications
`Alone and With Symptomatic
`Gastroduodenal Ulcers
`
`.
`AIAII Patients
`
`El Celeomtio
`I mm
`
`.
`
`P=.02
`4mm
`
`- F=.09
`2011334
`
`11r1441 I
`
`
`
`
`3011441
`
`
`
`Fl Patients Not Taking Aspirin
`
`6 5
`
`4
`3
`2
`
`I
`
`0
`
`a?
`8
`5
`3.3
`‘2’
`E
`fi31:
`E
`
`a?
`
`5
`
`complication were assigned a diagnosis
`from the categories listed in Table 3.
`The annualized incidence ot'upper GI
`ulcer complications in celecoxib—
`treated patients was 0.76% (1 1 events!
`1441 patient—years) vs an incidence of
`1.45% (20 events/1384 patient-years)
`[or patients taking NSAIDs (P:.09;
`FIGURE 2A). The relative risk (RR) for
`celecoxib compared with NSAIDs was
`0.53 (95% CI. 0.26—1.11). The annu—
`alized incidence of upper GI ulcer com—
`plications plus symptomatic ulcers with
`celecoxib was 2.08% (30 events/1441
`patient-years) vs 3.54% (49 events!
`1384 patientvyears) for patients take
`ing NSAle (P: .02; Figure 2A). The RR
`[or celecoxib compared with NSAIDs
`was 0.59 (95% CI, 0.38-0.94).
`Inclusion ofthe 2 censored events in
`each group did not alter the interpreter
`Lion of results. For upper GI ulcer com—
`plications, the rates without censoring
`were 0.90% (13 events/1441 patient-
`years) and 1.59% (22 events/1384- pa-
`tient—years) for celecoxib and NSAIDs,
`respectively (P=.11). For upper GI ul-
`cer complications plus symptomatic ulr
`cers. the rates were 2.22% (32 event5/
`
`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 complications in ei—
`ther treatment group (RR, 0.2 and 0.6 for
`patients treated with celecoxib and
`NSAle, respectively; P: .13 and P: .2?)
`
`GI Toxicity With Aspirin Use
`Based on time—to—event analyses using
`a Cox proportional hazard model, low—
`dosage aspirin use was found to have a
`significant effect on the incidence ol'up-
`per GI ulcer complications in celecoxibr
`treated patients. Within the celecoxib
`treatment group, the RR of an upper GI
`ulcer complication was 4.5 with low-
`dosage aspirin use: 6 events in 833 pa—
`tients taking lowrdosage aspirin vs 5
`events in 3154 non—aspirin users
`(P=.01). Low—dosage aspirin use did not
`have asignilicant eIIect on the rate ol'up-
`per GI ulcer complications in patients
`receiving NSAIDs (RR, 1.7; P229).
`When the non—aspirin-using co-
`hort was examined, 2 upper GI ulcer
`complications were censored (I in each
`
`— T
`
`a
`4
`153
`9 3
`3
`fl
`2
`3
`C
`‘1
`
`I _
`0
`
`6_
`
`P=.04
`
`'
`
`1411101
`
`some I
`
`
`
`
`
`
`
`0 Patients Taking Aspirin
`
`
`
`able 3. Adjudicated Cases Meeting and Not Meeting Prespecialized Definitions of
`Gastroduodenal Ulcers and Ulcer Compiications“
`Gelecoxib Group
`NSAID Group
`
`(n = 3937]
`(n = 3981)
`
`Total No. of cases adiudicatecl
`1 11
`1491
`No. of adjudicated cases not meeting the definition
`of a gastroduodenal ulcer or ulcer complication
`Esophageal disease
`23
`21
`
`Gastroduodenitis
`12
`21
`
`Colonic or small bowel disease
`10
`r
`
`Nonulcer bleeding
`1O
`17
`Miscellaneous GI symptoms
`18
`20
`Anemia
`5
`12
`
`Choleiithiasis
`1
`0
`
`Total
`79
`98
`No. of adjudicated cases meeting the definition
`of a gastroduodenal ulcer or ulcer complication
`
`Gastroduodenal ulcers
`1%
`29
`
`Ulcer complicationsi
`13
`22
`
`Upper GI bleeding
`10
`20
`Perforation
`0
`0
`
`Gastric outlet obstruction
`1
`0
`
`Total 51 32
`
`I"NSND indicates nonstoroidal anti-inflammatory drug; GI. gastrointestinal.
`Numbers above bars indicate events per patient-
`tP<.001 vs celecoxib group.
`IFour ulcer complications [2 in the celecoxib group and 2 in the NSAID group] were censored from the analysis oe-
`years of exposure. NSAIDs indicates nonsteroidal anti-
`oauso of the timing of the event based on a mun—specified definitions.
`inflammatory drugs.
`
`|
`
`P- 02
`_'
`
`|
`32/1101
`
`iariids
`
`l
`
`.
`
`,fl‘
`117283
`
`14293
`
`
`
`.
`
`
`p- 92
`'
`erase W233
`
`
`
`
`
`5-
`4*
`
`2
`
`39
`as
`8
`a
`E 3-
`E
`3C
`fi
`&
`
`"0
`
`Ulcer Complications
`Symptomatic
`Ulcers and
`Ulcer Complications
`
`©2000 American Medical Association. All rights reserved.
`
`(Reprinted) .IAMA. September 13. ZOOO—VUI 284. No. 10 1251
`
`Downloaded From: httpirrjamaJamaneh-rorkxomr by a Reprints Desk User on 0300121115
`
`Page 5 of 9
`
`Patent Owner Ex. 2044
`
`Mylan v. Pozen
`lPR2017-01995
`
`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 syrnp-
`tomatic ulcers and/or upper GI compli—
`cations were not significantly different
`in patients taking celecoxib vs NSAle.
`For upper GI complications. the ob—
`served rates were 2.01% for patients tak-
`ing celecoxib vs 2.12% for patients tak-
`ing NSAle (6 events/298 patient-
`years vs 6 events/283 patient—Years,
`respectively; P=.92). For upper GI ul—
`cer complications plus symptomatic ul—
`ccrs. the observed rates were 4.70% for
`patients taking celecoxib vs 6.00% for
`patients taking NSAle (14 events/298
`patientryears vs 17 events/283 patientr
`years, respectively; P: .49). lncluding the
`2 censored events (I in each group), the
`rates were 2.35% and 2.47%, respec-
`tively, for upper GI ulcer complica—
`[ions and 5.03% and 6.36%, respecr
`tively, for upper GI ulcer complications
`plus symptomatic ulcers.
`
`other Adverse Effects
`
`Adverse ellects With an tnctdence 01 at
`least 5% in either treatmentgroup dur-
`mg the ormonth treatmentpet-tod were
`_G1 Syfnpwmsi upper ”51"““0‘7 “a“
`infection or related symptoms, head-
`ache, and rash. Adverse effects caus-
`ing withdrawal with an incidence ofat
`least 1% in either treatment group were
`GI symptoms, rash, and elevated trans-
`aminase levels. For these categories, ce—
`lecoxib was associated with equiva—
`lent or lower incidences of adverse
`effects and withdrawals compared with
`NSAID therapy, with the exceptions of
`rash and pruritus (TABLE 4).
`S
`.
`d
`ffects (re resentin
`g
`eliloué a yerse e
`.
`P
`.
`hOSPIlallzaflonS 0‘ mahgmnmes de'
`lecmd during [he 6'm0mh treatment Pe-
`l‘lOd) were reported for 4.3% Of cele-
`COXib patients (l72 eventsf3987
`patients) and 4.2% of NSAID patients
`(168 events/3981 patients). The most
`common serious adverse effects in pa-
`lients taking celecoxib and NSAlewere
`accidental fractures (7 and 8 events, re-
`spectively), back pain (8 and 8 events,
`respectively), pneumonia (9 and 9
`events, respectively), cardiac failure (9
`and 10 events, respectively), myocar—
`dial infarction (IO and 10 events, re—
`
`of upper GI ulcer complications plus
`symptomatic ulcers in patients not tak-
`ing aspirin was also significantly lower
`with celecoxib than with NSAIDS
`
`(1.40% [16 events/1143 patient-
`yearsl vs 2.91% [32 events11101 pa—
`tient-years]; P: .02; Figure 213). The RR
`for celecoxib compared with NSAIDs
`was 0.48 (95% CI, 0.28-0.89).
`Inclusion of the 1 censored event in
`each group did not alter 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 NSAle,
`respectively (P:.05). For upper GI ul—
`cer complications plus wmptornatic ul-
`cers, the rates were 1.49% (17 events!
`1143 patient-years) and 3.00% (33
`events/1101 patient—years) for cele—
`coxib and NSAIDs, respectively (P=.02).
`
`— T
`
`
`able 4. Adverse Effects During the 6-Month Treatment Period“
`All Patients
`Patients Not Taking Aspirin
`l—I l—I
`Celecoxib Group NSAID Group Celecoxib Group NSAID Group
`Adverse Effects
`(n = 3987)
`(n = 3981]
`(n = 3154)
`(n = 3169)
`Gastrointestinal
`
`Dyspepsia
`575 (14-4)
`640116-01
`427113.51
`496115-7l‘i'
`
`Abdominal pain
`337 (9.7)
`522 (13.1)t
`286 (9.1)
`395 (12.5)1-
`
`Diarrhea
`37319-4)
`392 (93)
`23319-1)
`293 (92)
`
`Nausea
`27? (6.9]
`370 (9.311'
`213 [6.8)
`277 (8.711-
`
`Constipation
`63 (1.7)
`234 (5.9)1
`48 (1.5)
`172 (5.401
`
`Total
`1250 (31.4)
`1465 (30.8)1
`942 (29.9)
`1127 {356)t
`
`Withdrawals
`345 (8.7)
`427110.?”
`252 (8.0)
`321 {wilt
`
`Hepagtated 86mm ALT
`2310-5)
`38 (231
`15 [0.6)
`68 (2'1”
`
`Elevated serum AST
`13 [0-5)
`73 (1'3”
`13 [0.4)
`60 mm
`
`Total
`24 (0.s)
`90 (2'3”
`1 3 (0.s)
`72 {2.3”
`
`Withdrawals
`2 (<01)
`46(1.2)1-
`2 (<01)
`36 (1.1)1
`Bleeding-related
`
`Anemia
`81 (2.0)
`1?5 (4.4))
`59 (1.9)
`123 (3.9)1
`
`Eochvmosis
`28 (0.?)
`32 (0.0)
`22 (0.7)
`26 [0.8]
`Hematochezia
`17 (0.4)
`40 (1 on
`11 (0.3)
`29 (0.911
`
`Total
`123 (3.1)
`238 (0.0)1
`90 (2.9)
`171 (5.4)1
`
`Withdrawals
`16 (0.4)
`26 (0.?)
`13 (0.4)
`19 (0.6)
`
`Renal
`_
`Penphera'edema
`113(2'8)
`138 (3'5)
`90(2'9)
`108(3'4’
`
`
`Hymnamio”
`66 (1‘7)
`90 [2‘3”
`50 [I '6)
`55 {2‘1}
`
`Tgerlsed ”gamma level
`23 (0‘7)
`48 (1‘2”
`20 (0'6)
`33 (1‘0)
`
`_ a
`200 (5‘0)
`263 [6‘6”
`155 (4'9)
`198 [6‘2”
`Withdrawals
`44 (1.1)
`41 (1.0)
`37 (1.2)
`32 (1.0)
`Cardiovascular
`
`Cerebrovascmaraocident
`5 (0.1)
`10 (0.3)
`a (<01)
`5 (0.2)
`
`Myocardial infarction
`10 (0.3)
`1 1 (0.3)
`3 (<01)
`4 (0.1)
`
`Angina
`24 (0‘5)
`22 (0.6)
`10 [03)
`7 (02)
`Total
`3709)
`39 (1.0)
`13(075)
`14(04)
`
`Withdrawals
`12(03)
`13 (0.3)
`9(03)
`5 ((12)
`Cutaneous
`
`Has"
`21315-5}
`1m (2531
`130 [5-7)
`91 (3931
`Pm'ims
`91 12-3)
`59 (1 5”
`79 19-3)
`44 {1 Ali
`
`Urticaria
`22 {0-5}
`14 [0-4)
`13 [0-5)
`13 {0-4}
`
`Total
`293 (7‘5)
`153 (4-1”
`241 [7-6]
`13591-3”
`Withdrawals
`109 (2.?)
`49 (1.2))
`92 (2.9)
`43 (1.4)1-
`*Data are given as No. (its) of patients. Categories are nonadditivs; patterns may have experienced more than 1 ad-
`verse event in each category. NSAID indicates none/toroidal anti-inflammatory drug: ALT. alanine aminotransferase:
`and AST. asoanate aminotransferase.
`TP.~=.DS vs oelecoxib group.
`
`1252 JAMA, September 1 3, ZOOO—NOI 284, No 10 (Reprinted)
`
`©2000 American Medical Association. All rights reserved.
`
`Downloaded From: http:tfjama.jamanetwork.eomr by a Reprints Desk User on 03120121115
`
`Page 6 of 9
`
`Patent Owner Ex. 2044
`
`Mylan v. Pozen
`lPR2017-01995
`
`Page 6 of 9
`
`Patent Owner Ex. 2044
`Mylan v. Pozen
`IPR2017-01995
`
`

`

`
`
`GI TOXICITY WITH CELECOXIB VS NSAIDS FOR ARTHRITIS
`
`— F
`
`igure 3. Patients With Decreases in
`Hematocrit andlor Hemoglobin at 6 Months
`
`El Celeooxib
`
`I NSAIDS
`P<,[x)1
`1
`107/348?
`
`P<.00l
`l—l
`
`135/3651
`
`
`
`.
`
`4'0
`3 5
`30
`
`d)0
`5°: 2.5
`g 2.0g
`:3 1.5
`1.0
`0.5
`
`.
`0
`Ail Patients
`Patients Without
`GI Disease
`
`5013582
`
`
`
`
`58/3701
`
`
`
`
`
`Data are shown for patients with decreases from pre-
`treatment levels in hematocrit of 10