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7/25/2019 Journal of International Medical Research 2012 Essex 1357 70
1/14
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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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
physicians global assessments of arthritis
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
physicians global assessments of arthritis
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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Celecoxib versus naproxen in osteoarthritis of the knee
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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Celecoxib versus naproxen in osteoarthritis of the knee
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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