Journal of International Medical Research 2012 Essex 1357 70

7/25/2019 Journal of International Medical Research 2012 Essex 1357 70

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The Journal of International Medical Research

2012; 40: 1357 1370

1357

Efficacy and Tolerability of Celecoxib

versus Naproxen in Patients withOsteoarthritis of the Knee: a Randomized,

Double-blind, Double-dummy Trial

MN ESSEX, P BHADRA AND GH SANDS

Pfizer Inc., New York, New York, USA

OBJECTIVE: To assess the efficacy and

tolerability of celecoxib versus naproxen

in patients with osteoarthritis (OA) of the

knee. METHODS: This 6-month,

randomized, double-blind, double-dummy

trial was conducted at 47 centres in the

USA. Patients with OA of the knee were

randomized to receive 200 mg celecoxib

orally once daily or 500 mg naproxen

orally twice daily. The primary endpoint

was defined as a 20% improvement from

baseline to 6 months in Western Ontario

and McMaster Universities (WOMAC) OA

total score. RESULTS: A total of 586 out of

589 randomized patients received at least

one dose of celecoxib (n = 294) or naproxen

(n = 292). The primary endpoint (6-month

response rate) was achieved by 52.7% and

49.7% of patients in the celecoxib and

naproxen treatment groups, respectively.

Significantly fewer discontinuations due to

gastrointestinal adverse events occurred in

patients receiving celecoxib than in those

receiving naproxen (4.1% versus 15.1%,

respectively). CONCLUSIONS: Over the 6-

month study period, celecoxib provided

similar improvements in OA symptoms to

naproxen. In addition, celecoxib provided

better upper gastrointestinal tolerability

than naproxen.

KEY WORDS: CELECOXIB; EFFICACY; KNEE; NAPROXEN; NONSTEROIDAL ANTI-INFLAMMATORY DRUGS;

OSTEOARTHRITIS; TOLERABILITY: WOMAC SCORE

IntroductionOsteoarthritis (OA) of the knee is a major

cause of pain and physical disability in the

elderly,1 with symptomatic disease affecting

10% of men and 13% of women aged 60

years in the USA.2 While changes in the

musculoskeletal system associated with

aging increase the propensity for OA, factorssuch as joint injury, obesity and genetic

predisposition are important in determining

which joints are affected and the severity of

disease.1,3,4 The prevalence of OA of the knee

is expected to increase as obesity rates rise

and the population continues to age.2,5

Many patients with OA take medication

for long periods of time and have a number

of comorbidities requiring the use of

concomitant medication, increasing the

likelihood of adverse events6 10 includinggastrointestinal (GI) injury.11,12 There is an

increasing demand for more effective and

safer OA treatments. Clinical guidelines

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MN Essex, P Bhadra, GH Sands

Celecoxib versus naproxen in osteoarthritis of the knee

often recommend the use of nonsteroidal

anti-inflammatory drugs (NSAIDs) for the

relief of pain and inflammation associated

with OA.13 19 The cyclo-oxygenase 2 (COX-

2) selective NSAID celecoxib has proven

efficacy in relieving pain and improving

physical function in patients with OA.20 26

Many studies of NSAIDs for the treatment

of OA have been relatively short-term (6 12

weeks),20,22,23,25,27,28 but patients with

arthritis generally take medication for longer

periods. In order for physicians to employ

evidence-based medicine, data from longer

treatment periods are needed. The present 6-

month, randomized, double-blind, double-

dummy trial was conducted in 47 centres in

the USA in patients with symptomatic OA of

the knee in order to evaluate the efficacy and

tolerability of daily celecoxib compared with

naproxen.

Patients and methodsPATIENTSThis 6-month, multicentre, randomized,

double-blind, double-dummy trial was

conducted in 47 centres in the USA between

March 2004 and January 2005. Men and

women aged 40 years, with OA of the knee

diagnosed according to American College of

Rheumatology criteria29 and who were

determined by their physician to be eligible

for chronic NSAID therapy, were consideredfor inclusion. Patients whose knee OA was in

a flare state and who demonstrated

functional capacity classification29 grades I,

II or III at the baseline visit were eligible for

inclusion. Women of childbearing age were

required to be using adequate contraception,

not breastfeeding and to have a negative

urine pregnancy test within 14 days before

the baseline visit.Exclusion criteria were: (i) acute flare of

inflammatory arthritis or gout/pseudogout

within the past 2 years; (ii) acute trauma at

the index joint within the past 3 months

with active symptoms; (iii) surgery on the

index joint within the past 6 months or

surgery on the nonindex joint within the

past 3 months; (iv) anticipated need for

surgery or another invasive procedure on the

index and/or nonindex joints during the

study; (v) physical therapy on the index joint

or use of a mobility assisting device (e.g.

cane) for < 6 weeks prior to the screening

visit; (vi) use of a walker-assisting device;

(vii) use of oral (at 4 weeks before the first

dose of study medication), intramuscular (at

2 months), intra-articular (at 3 months)

or soft tissue (at 2 months) injections of

corticosteroids; (viii) intra-articular

injections of hyaluronic acid in the index

joint 9 months before the first dose of study

medication; (ix) use of paracetamol 24 h

before the baseline visit; (x) use of

anticoagulants or lithium; (xi) use of

glucosamine and/or chondroitin sulphate,

unless the dose had been stable for > 4

months or discontinued for 4 months; (xii)

known sensitivity to nonselective or COX-2

selective NSAIDs, sulphonamides, aspirin or

related compounds; (xiii) oesophageal,

gastric, pyloric channel or duodenal

ulceration 60 days prior to the first dose of

study medication; (xiv) history of GI

perforations, obstructions or bleeding; (xv)

active GI disease; (xvi) renal or hepaticdisease; (xvii) significant bleeding disorder;

(xviii) diagnosis of unstable cardiovascular

disease 6 months prior to study entry; or

(xix) clinically significant laboratory

abnormalities at screening.

The use of nonstudy NSAIDs, antacids,

histamine-2 receptor antagonists or proton-

pump inhibitors was prohibited, with the

exception of aspirin at a stable dose of 325mg/day for cardiovascular prophylaxis and

calcium-containing antacids for osteoporosis

prevention. The use of analgesics



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(paracetamol dose of 2 g/day for 3

consecutive days) for reasons other than

arthritis was permitted if absolutely

necessary, but not within 24 h of any visit.

Topical pain relief to nonindex joints was

allowed except within 48 h of any visit.

STUDY DESIGN

Patients were randomized at study entry in a

1 : 1 ratio to receive either 200 mg celecoxib

orally once daily or 500 mg naproxen orally

twice daily, using a computer-generated

randomization scheme. All patients took

study medication in the form of capsules

(active drug or placebo) twice daily to

maintain blinding.

There were five study visits, defined as:

screening (1 14 days prior to the first dose

of study medication); baseline (within 24 h

before the first dose of study medication;

index joint designated at this visit); month 1

(days 27 33 after the first dose of study

medication); month 3 (days 86 94 after the

first dose of study medication); and month 6

(days 175 185 after the first dose of study

medication). Patients completed a 2-day

washout period for analgesic medication

before the baseline visit. Those who stopped

taking study medication were encouraged to

remain in the study and complete the

scheduled visits, but could be discontinued

from the study at any time by theinvestigator or at the patients request.

The institutional review board and/or an

independent ethics committee at each centre

approved the protocol. The study was

conducted in accordance with the

Declaration of Helsinki,30 International

Conference on Harmonisation good clinical

practice guidelines,31 the US Food and Drug

Administration (FDA) regulations32 andlocal regulatory requirements. All patients

provided written informed consent prior to

enrolment.

STUDY ENDPOINTS

The primary efficacy endpoint was the

Western Ontario and McMaster Universities

(WOMAC)33 total score response rate at

month 6, defined as a 20% improvement in

total WOMAC OA score from baseline to 6

months. The WOMAC scale includes three

subscales that are combined to generate a

total score. The three subscales are: pain (five

questions, each response ranging from 0 4);

stiffness (two questions, each response

ranging from 0 4); and physical function

(17 questions, each response ranging from 0

4). A reduction in score indicates

improvement. Those patients who did not

complete 6 months of treatment were

considered nonresponders for the purposes of

this study.

Secondary efficacy endpoints included

changes from baseline to month 6 in: total

and subscale WOMAC scores; the patients

and physicians global assessments of

arthritis; and the patients assessment of

arthritis pain using a 0 100 mm visual

analogue scale (VAS; 0 mm, no pain; 100

mm, very severe pain). For the patients

global assessment of arthritis, patients rated

their condition on a scale of 1 5 (1, very

good [asymptomatic and no limitation of

normal activities]; 5, very poor [very severe,

intolerable symptoms and inability to carry

out normal activities] in answer to thequestion: Considering all the ways the OA

in your knee affects you, how are you doing

today? The physicians global assessment of

arthritis was a similar five point scale,

indicating the physicians opinion based on

the patients disease signs. The patients and

physicians global assessments of arthritis

and the VAS data were assessed at baseline

and months 1, 3 and 6.Other endpoints included the patients

assessment of arthritis pain response rate at

month 6 (a 20% improvement in VAS score



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from baseline) and the change from week 1

to month 6 in GI distress score for patients

remaining on study medication for 6 months

compared with those who prematurely

discontinued study treatment. GI distress

score was measured on a VAS scale of 0 100

mm (0 mm, no distress; 100 mm, complete

distress).34,35 Patients were required to record

GI distress scores weekly in a diary and

changes were calculated using the value at

week 1 as baseline.

SAFETY ASSESSMENTS

Safety assessments included monitoring for

adverse events (adverse drug reactions,

illnesses with onset during the study and

exacerbation of previous illnesses) and any

clinically significant changes in vital signs at

screening, baseline, and months 1, 3, and 6

or early termination. Adverse events were

summarized using the Medical Dictionary

for Regulatory Affairs preferred terms36 and

were subjectively classified by the

investigator as mild, moderate or severe.

STATISTICAL ANALYSES

The sample size was calculated based on the

primary efficacy endpoint (total WOMAC

score response rate). Based on assumptions

derived from studies carried out in the

celecoxib development programme and

postmarketing information it wasanticipated that the response rates for

celecoxib and naproxen would be

approximately 37% and 25%, respectively. A

sample of 250 patients per treatment group

would, therefore, provide 80% power for a

two-sided test at the 5% level of significance.

Efficacy analyses were performed on the

modified intent-to-treat (mITT) population

(all randomized patients who received atleast one dose of study medication and had

at least one postbaseline follow-up efficacy

measurement), and safety/tolerability

analyses were performed on the safety

population (all randomized patients who

received at least one dose of study

medication).

The CochranMantelHaenszel test was

used to analyse the primary efficacy

endpoint, the changes in the patients and


and patients assessment of arthritis pain

(VAS) from baseline to month 6, and the

patients assessment of arthritis pain

response rate at month 6. A general linear

model was used to analyse the changes in

total and subscale WOMAC scores from

baseline to month 6, and the change in GI

distress score from week 1 to month 6.

Descriptive statistics were used to summarize

treatment-emergent adverse events. All

statistical tests were two-sided and were

performed using the SAS statistical package

version 8.0 or higher (SAS Institute Inc.,

Cary, NC, USA). A P-value < 0.05 was

considered statistically significant.

ResultsA total of 589 patients were randomized to

the two treatments (celecoxib n = 296,

naproxen n = 293); two patients in the

celecoxib group and one in the naproxen

group did not receive study medication but

underwent at least one postbaseline efficacy

measure. The safety and mITT populations,therefore, comprised 586 patients (celecoxib

n = 294, naproxen n = 292). Demographic

and baseline clinical characteristics of the

two study groups are shown in Table 1. The

majority of patients were Caucasian females.

There were no statistically significant

between-group differences in demographic

or clinical characteristics at baseline.

A similar percentage of patients remainedon study medication for 6 months in both

groups (celecoxib 202/294 [68.7%],

naproxen 189/292 [64.7%]; Fig. 1). The



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median duration of treatment was 177.5

days (range 1 253 days) in the celecoxib

group and 176.0 days (range 1 203 days) in

the naproxen group. Fewer patients in the

celecoxib group than in the naproxen group

discontinued treatment because of anadverse event considered by the investigator

to be related to study medication (18/294

[6.1%] and 38/292 [13.0%], respectively).

Information regarding concomitant

medication use was provided by 284 patients

in the celecoxib group and 283 patients in

the naproxen group. Concomitant

medication was used by 246 patients in each

group (86.6% and 86.9% in the celecoxiband naproxen groups, respectively). The

most commonly used medications in the

celecoxib and naproxen groups were aspirin

(55 and 61 patients, respectively),

multivitamins (39 and 38 patients,

respectively) and tocopherol (25 and 30

patients, respectively).

There was no significant between-group

difference in response rate, with similarnumbers of patients in the celecoxib and

naproxen groups having a 20%

improvement in total WOMAC score from

baseline to month 6 (Table 2). There were

also no significant between-group differences

in response rate in the pain, stiffness, or

physical function WOMAC subscales.

Improvements in both the patients and

physicians global assessments of arthritisfrom baseline to month 6 were similar in

both groups (Table 3). In addition, there was

no significant between-group difference in

TABLE 1:Demographic and clinical characteristics at baseline of patients with osteoarthritis (OA) ofthe knee who were randomized to receive either 200 mg celecoxib orally once daily or500 mg naproxen orally twice daily for 6 months

Celecoxib NaproxenCharacteristic n = 296 n = 293

Age, yearsa 60.0 10.7 (39 92) 60.7 11.1 (39 89)Genderb

Males 104 (35.1) 95 (32.4)Females 192 (64.9) 198 (67.6)

Race/ethnic originb

Caucasian 210 (70.9) 213 (72.7)Black 36 (12.2) 34 (11.6)

Asian 28 (9.5) 24 (8.2)Other 22 (7.4) 22 (7.5)Time from diagnosis of OA in index 7.2 8.1 (0.003 51.44) 8.5 9.0 (0.003 52.35)

knee to screening visit, yearsAmerican College of Rheumatology criteria29

functional capacity classificationb

I 5 (1.7) 6 (2.0)II 224 (75.7) 217 (74.1)III 67 (22.6) 70 (23.9)IV 0 (0.0) 0 (0.0)

WOMAC33 OA total scorea 53.9 14.8 (11 90) 54.3 15.1 (15 93)

Data presented as mean SD (range), or n (%) of patients.WOMAC, Western Ontario and McMaster Universities.No statistically significant between-group differences (P0.05): ageneral linear model with treatment andcentre as factors; bCochranMantelHaenszel test stratified by centre.



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the least square mean change in patients

assessment of arthritis pain (VAS score) from

baseline to month 6 (39.3 and 41.2 for

celecoxib and naproxen, respectively). The

VAS pain score response rates (20%

improvement from baseline to month 6)

were also not significantly different between

the two groups (63.2% and 58.6%,

respectively). There were also no significantbetween-group differences in the change in

GI distress score throughout the study period

(Fig. 2).

Serious adverse events were experienced

by 3.1% (9/294) of patients in the celecoxib

group and by 2.7% (8/292) in the naproxen

group (Table 4). The majority of serious

adverse events were considered unrelated to

the study drugs. Serious treatment-related

adverse events occurred in 0.7% (2/294) of

patients in the celecoxib group (one case

each of atrial fibrillation and anaphylaxis)and 0.3% (1/292) in the naproxen group

(thrombocytopenia). There was one reported

serious GI adverse event (haemorrhage),

FIGURE 1: Flow chart showing the process of screening, treatment randomization andtreatment withdrawals for the patients with osteoarthritis of the knee who wererandomized to receive either 200 mg celecoxib orally once daily or 500 mg naproxenorally twice daily for 6 months

Screened(n= 747)

Not randomized(n= 158)

Randomized(n= 589)

Celecoxib 200 mg once daily(n= 296)

294a

patients receivedtreatment and were evaluable

for adverse events

202 patients remained onstudy drug for 6 months

44 patients discontinueddue to adverse events

Naproxen 500 mg twice daily(n= 293)

292a

patients receivedtreatment and were evaluable

for adverse events

189 patients remained onstudy drug for 6 months

64 patients discontinueddue to adverse events

aTwo patients in the celecoxib group and one in the naproxen group did not receive studymedication but underwent at least one postbaseline efficacy measure, so the safety andmodified intent-to-treat populations comprised 586 patients (celecoxib n= 294, naproxenn= 292)



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which occurred in a patient receiving

naproxen, but this was not considered

treatment-related. Serious cardiovascular

adverse events were reported in five patients;

three in the celecoxib group (exacerbation of

coronary artery disease; severe bradycardia

and arrhythmia; atrial fibrillation) and two

in the naproxen group (small vesselischaemic disease; chest pain). The episode

of atrial fibrillation in the celecoxib group

was the only serious cardiovascular adverse

event considered to be treatment related by

the investigator. There were no myocardial

infarctions, strokes or deaths during the

study period.

The numbers of all-cause and treatment-

related adverse events were similar in bothgroups (Table 4), with GI adverse events

being the most commonly reported (Table 5).

When GI disorders were stratified by severity,

fewer moderate or severe GI adverse events

occurred in the celecoxib group than the

naproxen group (37 moderate/seven severe

and 54 moderate/13 severe, respectively). In

addition, fewer patients in the celecoxib

group than in the naproxen group

experienced moderate or severe nausea (six

and nine patients, respectively), abdominalpain (one and six patients, respectively), or

dyspepsia (19 and 21 patients, respectively).

The numbers of patients discontinuing

due to all-cause and treatment-related

adverse events were lower in the celecoxib

group than in the naproxen group (Table 4).

The most common adverse events that led to

discontinuation were GI disorders (Table 5).

Although GI adverse events were reported atsimilar frequencies in the two treatment

groups they were less often cited as the

reason for discontinuation by patients

TABLE 2:Change from baseline to month 6 (or early termination) in total and subscale WesternOntario and McMaster Universities (WOMAC) osteoarthritis scores33 in patients withosteoarthritis of the knee who were randomized to receive either 200 mg celecoxib orallyonce daily or 500 mg naproxen orally twice daily for 6 months (modified intent-to-treatpopulation, n = 586)

Celecoxib NaproxenWOMAC total or subscale n = 294 n = 292

Totala

Respondersb, n (%) 155 (52.7) 145 (49.7)LSM change (SE) 22.2 (1.1) 22.6 (1.1)

Pain subscaleRespondersb, n (%) 163 (55.4) 147 (50.3)

LSM change (SE) 4.9 (0.2) 5.0 (0.2)Stiffness subscaleRespondersb, n (%) 153 (52.0) 150 (51.4)LSM change (SE) 1.8 (0.1) 1.9 (0.1)

Physical function subscaleRespondersb, n (%) 155 (52.7) 146 (50.0)LSM change (SE) 15.4 (0.8) 15.7 (0.8)

aSum of pain, stiffness and physical function subscale scores.bPatients with 20% decrease (improvement) in WOMAC score from baseline to month 6.LSM, least squares mean.No statistically significant between-group differences (P0.05); general linear model with change frombaseline as dependent variable and factors for treatment, centre and baseline WOMAC score (total orsubscale, as appropriate) as covariates.



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receiving celecoxib than by those receiving

naproxen (P < 0.0001; Table 5). Upper

abdominal pain, abdominal distension,

constipation, dyspepsia, gastro-oesophagealreflux disease and nausea were among those

symptoms associated with the largest

between-group differences in rate of

discontinuation for GI adverse events. When

these GI adverse events were combined,

celecoxib was significantly better tolerated

by patients than naproxen (P= 0.0028).

DiscussionIn this 6-month trial, 200 mg celecoxib oncedaily demonstrated similar efficacy to 500

mg naproxen twice daily in the treatment of

symptoms associated with OA. This finding

was consistent across various measures,

including a 20% improvement in WOMAC

scores, patient assessment of arthritis pain(VAS score), and both the patients and


from baseline to month 6. These 6-month

study results support findings from 12-week

trials in OA patients in which 200 mg

celecoxib once daily demonstrated similar

efficacy in terms of pain relief and

improvement in physical function to 500 mg

naproxen twice daily.20,22,25Celecoxib was generally well tolerated,

with a similar incidence of general adverse

events to that seen with naproxen. The

TABLE 3:Patients and physicians global assessments of arthritis at baseline, month 6 (or earlytermination) and change from baseline in patients with osteoarthritis of the knee whowere randomized to receive either 200 mg celecoxib orally once daily or 500 mgnaproxen orally twice daily for 6 months

Celecoxib Naproxen

Global assessment measure Patient Physician Patient Physician

Baseline, n 296 296 293 293Very good 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0)Good 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0)Fair 65 (22.0) 72 (24.3) 74 (25.3) 70 (23.9)Poor 200 (67.6) 201 (67.9) 180 (61.4) 194 (66.2)

Very poor 31 (10.5) 23 (7.8) 39 (13.3) 29 (9.9)

Month 6, na 285 285 285 285Very good 47 (16.5) 41 (14.4) 59 (20.7) 48 (16.8)Good 126 (44.2) 136 (47.7) 122 (42.8) 138 (48.4)Fair 95 (33.3) 87 (30.5) 85 (29.8) 82 (28.8)Poor 14 (4.9) 18 (6.3) 14 (4.9) 16 (5.6)

Very poor 3 (1.1) 3 (1.1) 5 (1.8) 1 (0.4)Change from baseline, na 285 285 285 285

Improvedb 152 (53.3) 155 (54.4) 155 (54.4) 156 (54.7)No change 130 (45.6) 127 (44.6) 125 (43.9) 128 (44.9)

Worsenedc 3 (1.1) 3 (1.1) 5 (1.8) 1 (0.4)

Data presented as n (%) of patients.aPercentages based on the number of patients from the modified intent-to-treat population of 586 patients

for whom there were data at the month 6/early termination visit.bReduction of at least two grades or a change to very good.cIncrease of at least two grades or a change to very poor.No statistically significant between-group differences (P0.05); CochranMantelHaenszel test stratified bycentre.



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change in GI distress (VAS score) was similar

in the two treatment groups, but there were

fewer discontinuations due to GI adverse

events in patients receiving celecoxib than in

those receiving naproxen, suggesting

celecoxib may have a more favourable GI

tolerance profile than naproxen. The resultsof the present study are consistent with other

trials that have demonstrated improved GI

tolerance of celecoxib over nonselective

NSAIDs,20,21,25,37 and evidence suggests that

celecoxib is associated with fewer tolerance-

related GI adverse events than nonselective

NSAIDs.37 39 The current study was not

designed to evaluate differences between the

two drugs in the incidence of serious GI

events, such as bleeding or ulcer, but thesingle serious GI adverse event reported (GI

haemorrhage) in a patient receiving

naproxen was not deemed to be treatment-

FIGURE 2: Week by week change from baseline (week 1) in gastrointestinal (GI)symptoms, as measured by the GI distress score (visual analogue scale [VAS]), for thepatients with osteoarthritis of the knee who were randomized to receive either 200

mg celecoxib orally once daily or 500 mg naproxen orally twice daily for 6 months(compiled from the modified intent-to-treat population of 586 patients for whomthere were data; n values shown in the Fig.)

B Patients who prematurely discontinued treatment followed to the time of discontinuation

A Patients who completed the study

4

2

0

2

4

6

Changein

GIdistress(VAS)

8

10

12

14

16

18

20

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15

Time in study (weeks)

Treatment group Celecoxib 200 mg once daily (n= 202)

Naproxen 500 mg twice daily (n= 189)

16 17 18 19 20 21 22 23 24 25 26 27 28 29 30

4

02

246

Changein

GIdistress(VAS)

810121416

1820

1

222426283032

2 3 4 5 6 7 8 9 10 11 12 13 14 15

Time in study (weeks)

Treatment group Celecoxib 200 mg once daily (n= 92)

Naproxen 500 mg twice daily (n= 103)

16 17 18 19 20 21 22 23 24 25 26 27



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related. Practitioners must balance these

current findings with the increased risk of

serious GI adverse events known to be

associated with NSAIDs.11,12

The occurrence of serious cardiovascular

adverse events was infrequent and similar in

the two treatment groups, although the

current study was neither designed nor

powered to investigate cardiovascularadverse events. There is evidence to suggest

that all NSAIDs may increase cardiovascular

risk to a similar level,8 10 and all

prescription NSAIDs, including celecoxib

and naproxen, have received the same

cardiovascular warning from the FDA.40 The

PRECISION trial, in which celecoxib is being

compared with naproxen and ibuprofen, is

expected to answer the question of overallbenefitrisk of NSAIDs in the treatment of

arthritis pain. Given the importance of GI

and cardiovascular safety with NSAID use,

American College of Rheumatology19 and

National Institute for Health and Clinical

Excellence16,41 guidelines stress the

importance of the assessment of relevant risk

factors in individual patients prior to

treatment selection.

The current study assessed a wide range of

patient-reported outcomes covering efficacy

and safety over a 6-month treatment period.Although this trial was completed several

years ago, data regarding long-term efficacy

and tolerability of treatments for conditions

such as OA remain relevant for current

patient care. Patients must be able to tolerate

medication in order to receive the efficacy

benefits, and information on relative

tolerability is useful when clinicians make

treatment decisions for their patients. Astrength of the present study was the use of

naproxen, one of the most commonly used

NSAIDs in the USA, as the active comparator.

TABLE 4:Overview of treatment-emergent adverse events in patients with osteoarthritis of theknee who were randomized to receive either 200 mg celecoxib orally once daily or 500mg naproxen orally twice daily for 6 months (safety population, n = 586)

All-cause Treatment-related

Celecoxib Naproxen Celecoxib NaproxenAdverse event measure n = 294 n = 292 n = 294 n = 292

Totala 443 458 194 2341 193 (65.6) 197 (67.5) 124 (42.2) 142 (48.6)Seriousb 9 (3.1) 8 (2.7) 2 (0.7) 1 (0.3)Severec 25 (8.5) 24 (8.2) 10 (3.4) 10 (3.4)Discontinuation of treatment 44 (15.0) 64 (21.9) 30 (10.2) 49 (16.8)Dose reduction or temporary 9 (3.1) 11 (3.8) 6 (2.0) 6 (2.1)

discontinuation

Data presented as number of adverse events or n (%) of patients.Includes data up to 30 days after the last dose of study medication.

A total of two patients (one in each treatment group) discontinued due to adverse events that were nottreatment-emergent and are not included in this table.aAn adverse event occurring more than once in the same patient was counted once. A patient with two ormore adverse events contributed once to the count for each different adverse event.bAny adverse event that resulted in death, was life-threatening, required inpatient hospitalization orprolongation of existing hospitalization, resulted in persistent or significant disability/incapacity, or resulted incongenital anomaly/birth defect.cDetermined subjectively by the investigator (mild, moderate, or severe).



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In addition, the celecoxib dose used was that

approved and recommended by the FDA for

treatment of OA. The current study, therefore,

provides valuable information to help

physicians make treatment decisions for their

patients with OA.The findings of the current study are

limited by the short-term nature of the

treatment period relative to the years of drug

therapy usually received by patients with OA.

The efficacy and tolerability of celecoxib for

OA treatment over a 1 2-year period has,

however, been previously demonstrated.37,42,43

While these current data are limited to 6

months, the numerous efficacy andtolerability measures may provide useful

information for practitioners when choosing

therapy for their patients with OA.

TABLE 5:Incidence of all-cause treatment-emergent adverse events reported in 2% of patientswith osteoarthritis of the knee who were randomized to receive either 200 mg celecoxiborally once daily or 500 mg naproxen orally twice daily for 6 months (safety population,n = 586)

Patients reporting adverse Discontinuation due toevent adverse event

Celecoxib Naproxen Celecoxib NaproxenAdverse event n = 294 n = 292 n = 294 n = 292

Gastrointestinal disorders 128 (43.5) 138 (47.3) 12 (4.1) 44 (15.1)a

Dyspepsia 41 (13.9) 46 (15.8) 2 (0.7) 5 (1.7)Abdominal distension 21 (7.1) 16 (5.5) 2 (0.7) 4 (1.4)Diarrhoea 20 (6.8) 11 (3.8) 1 (0.3) 1 (0.3)

Nausea 19 (6.5) 24 (8.2) 2 (0.7) 6 (2.1)Abdominal discomfort 13 (4.4) 12 (4.1) 1 (0.3) 2 (0.7)Flatulence 11 (3.7) 12 (4.1) 0 (0.0) 1 (0.3)

Abdominal pain, upper 11 (3.7) 18 (6.2) 1 (0.3) 5 (1.7)Gastro-oesophageal reflux disease 9 (3.1) 6 (2.1) 0 (0.0) 3 (1.0)Constipation 7 (2.4) 10 (3.4) 1 (0.3) 4 (1.4)

Abdominal pain 5 (1.7) 8 (2.7) 1 (0.3) 3 (1.0)Stomach discomfort 5 (1.7) 6 (2.1) 0 (0.0) 1 (0.3)

General disorders 34 (11.6) 36 (12.3) 18 (6.1) 19 (6.5)Drug ineffective 13 (4.4) 11 (3.8) 12 (4.1) 11 (3.8)Peripheral oedema 5 (1.7) 11 (3.8) 1 (0.3) 2 (0.7)

Infections and infestations 29 (9.9) 37 (12.7) 1 (0.3) 2 (0.7)Nasopharyngitis 5 (1.7) 8 (2.7) 0 (0.0) 0 (0.0)Upper respiratory tract infection 4 (1.4) 7 (2.4) 0 (0.0) 0 (0.0)

Musculoskeletal disorders 45 (15.3) 29 (9.9) 9 (3.1) 7 (2.4)Arthralgia 18 (6.1) 10 (3.4) 2 (0.7) 2 (0.7)Back pain 9 (3.1) 4 (1.4) 1 (0.3) 1 (0.3)

Nervous system disorders 24 (8.2) 26 (8.9) 3 (1.0) 2 (0.7)Headache 8 (2.7) 6 (2.1) 2 (0.7) 1 (0.3)

Skin and subcutaneous disorders 11 (3.7) 13 (4.5) 1 (0.3) 1 (0.3)Rash 6 (2.0) 4 (1.4) 1 (0.3) 0 (0.0)

Data presented asn

(%) of patients.Includes data up to 30 days after the last dose of study medication.If a patient had more than one occurrence in the same category, only the most severe occurrence was included.aP< 0.0001 versus celecoxib group; Fishers exact test.



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Copyright 2012 Field House Publishing LLP

In summary, celecoxib provided relief of

OA symptoms and improvement in physical

function that was similar to naproxen over a

6-month period. In addition, fewer celecoxib-

treated patients discontinued therapy due to

GI adverse events compared with those

patients treated with naproxen, suggesting

that celecoxib provided favourable GI

tolerability. These data may be useful to

physicians when making treatment

decisions for their patients with OA.

AcknowledgementsThe study was sponsored by Pfizer Inc., New

York, New York, USA. Editorial support was

provided by Dr Christina Campbell,

PAREXEL, Uxbridge, UK and was funded by

Pfizer Inc.

Conflicts of interestDr Margaret Noyes Essex, Dr Pritha Bhadra,

and Dr George Sands are full-time employees

of Pfizer Inc.

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Authors address for correspondence

Dr Margaret Noyes EssexUS Medical Affairs Pain and Neuroscience, Pfizer Inc., 235 East 42nd Street, New York,

NY 10017, USA.

E-mail: [email protected]

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