The Journal of International Medical Research

2001; 29: 467 – 479

Comparative Efficacy and Safety of

Celecoxib and Naproxen in the
Treatment of Osteoarthritis of the Hip
AJ KIVITZ1, RW MOSKOWITZ2, E WOODS3, RC HUBBARD3, KM VERBURG3,
JB LEFKOWITH3 AND GS GEIS3
1
Altoona Center for Clinical Research; Altoona, PA, USA; 2Case Western Reserve University;
Cleveland, Ohio, USA; 3Pharmacia Corporation Research and Development, Skokie, IL, USA

Osteoarthritis (OA) is responsible for more naproxen 1000 mg/day; or placebo,

disability of the lower extremities in the
elderly than any other disease in the US.
The pain associated with OA is the
primary symptom leading to disability in
these patients. Current ACR guidelines
recommend consideration of acetaminophen
for mild-to-moderate pain and conventional
non-steroidal anti-inflammatory drugs
(NSAIDs) or COX-2 specific inhibitors for
moderate-to-severe OA symptoms. The aim of
this study was to compare the efficacy and
safety of the COX-1 sparing, COX-2 specific
inhibitor, celecoxib, with the conventional
NSAID naproxen, and placebo, in the
treatment of OA of the hip. In this
multicenter, randomized, placebo-controlled
trial, 1061 patients with symptomatic OA of
the hip were randomized to receive celecoxib
at doses of 100 mg, 200 mg, or 400 mg/day;
for 12 weeks. Patients were evaluated using
standard measures of efficacy at baseline,
2 – 4 days after discontinuing previous
NSAID or analgesic therapy, and after 2, 6,
and 12 weeks of treatment. All doses of
celecoxib and naproxen significantly
improved the symptoms of OA, at all time
points compared with placebo. This
sustained treatment effect of celecoxib was
dose dependent. In terms of pain relief and
improvement in functional capacity,
celecoxib 200 mg/day and 400 mg/day
were similarly efficacious and were
comparable to naproxen. Both drugs were
generally well tolerated. Celecoxib at a
dose of 200 mg/day is as effective as a
standard therapeutic dose of the con-
ventional NSAID, naproxen, in reducing
the pain associated with OA of the hip.

KEY WORDS: OSTEOARTHRITIS; CELECOXIB; COX-2 SPECIFIC INHIBITOR; DOSE REGIMEN

Introduction The primary indication for drug therapy

Approximately 20.7 million Americans have
been diagnosed with osteoarthritis (OA), the
most common of the arthropathies.1 OA of
the knee and of the hip account for more
lower extremity disability among the elderly
in the US than any other disease.2
in patients with OA of the hip is pain relief,
with most OA patients visiting a physician in
order to have their pain addressed.1,3 Recent
clinical trial data suggest that conventional
non-steroidal anti-inflammatory drugs
(NSAIDs) are more effective than
acetaminophen in treating the signs and

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 AJ Kivitz, RW Moskowitz, E Woods et al.
Celecoxib for OA of the hip
symptoms of OA and are the preferred agent
by patients.4,5 However, the clinical utility of
conventional NSAIDs is limited by the
significant incidence of serious adverse
events, including upper gastrointestinal
(UGI) ulceration and bleeding, that is
associated with their use.6 – 10 In addition, the
elderly, and therefore the majority of OA
patients, are at particularly high risk of
serious conventional NSAID-related UGI
adverse events.11 – 14 As there is currently no
cure for OA, with the exception of surgery,
at-risk patients may receive long-term
palliative conventional NSAID therapy,
further increasing the likelihood of a serious
UGI event.15
Conventional NSAIDs are non-specific
inhibitors of both isoforms of the enzyme
cyclo-oxygenase (COX-1 and COX-2), which
catalyze two key steps in the biosynthesis of
prostaglandins from arachidonic acid.16 – 18
As such, all conventional NSAIDs produce
mechanism-based gastrointestinal (GI)
toxicity and platelet inhibition via COX-1
inhibition.8
The COX-2 specific inhibitor, celecoxib
(Celebrex™), in contrast, spares COX-1
at therapeutic and supratherapeutic dos-
ages,19 – 23 providing effective anti-inflamma-
tory and analgesic efficacy,23 – 25 without the
increased risk of UGI and hematologic adverse
events characteristic of NSAID use, even
following long-term administration.7,25 – 28
The current study was performed to
establish that celecoxib, a COX-1 sparing
COX-2 specific inhibitor was equally effect-
ive to a non-selective NSAID, naproxen, in
patients with OA of the hip.
Subjects and methods
STUDY POPULATION
Adult out-patients were eligible to participate
if they fulfilled the ACR clinical and
radiographic criteria for a diagnosis of
468
primary OA of the hip,29 were in a functional
class of I, II, or III, and had symptomatic OA
flare at the baseline visit.30 Symptomatic OA
was demonstrated by a worsening of the
signs and symptoms of the disease following
discontinuation of conventional NSAID or
other analgesic medications, between the
screening and baseline visit, or by other
criteria for patients not receiving treatment.
Pre-menopausal women were included in
the study if they were not pregnant, and if
they were taking adequate contraceptive
measures. Patients were excluded from the
study if they had received oral,
intramuscular, intra-articular, or soft-tissue
injections of corticosteroids within 4 weeks of
receiving the first dose of study medication; a
known hypersensitivity to COX-2 inhibitors,
sulfonamides, or NSAIDs; received any
investigational medication within 30 days
of the first dose of study medication; taken
any NSAIDs or any analgesic within 48 hours
of the baseline assessment; or received
piroxicam and/or oxaprozin within 4 days
of the baseline assessment. Patients were
excluded if they had active, concomitant GI
tract, renal, hepatic, or coagulation disorders;
malignancy (unless in remission for 5 years);
or if they had been diagnosed with or treated
for esophageal/gastroduodenal ulceration
within 30 days of receiving study drug.
Patients diagnosed with inflammatory
arthritis, gout, or acute joint trauma at the
hip, or an anticipated need for surgery
during the study period were also excluded
from the study. Patients taking up to
325 mg/day aspirin for non-arthritic reasons,
or with a history of GI tract bleeding,
fibrositis, or fibromyalgia, were not excluded
unless they met other exclusion criteria.
STUDY PROTOCOL
This was a randomized, double-blind,
placebo-controlled, parallel-group trial,
 AJ Kivitz, RW Moskowitz, E Woods et al.
Celecoxib for OA of the hip
conducted over 12 months at 176 sites in
the US and Canada, in accordance with the
principles of good clinical practice and the
Declaration of Helsinki. The protocol was
approved by an institutional review board at
each site, and all patients provided written,
informed consent.
Patients discontinued conventional
NSAID therapy, and were screened at
baseline after a washout period of 2 – 4 days
(4 days for piroxicam and/or oxaprozin).
Patients were assessed for enrollment at
screening or baseline using the Western
Ontario and McMaster Universities
(WOMAC) Osteoarthritis (OA) Index,31 the
Arthritis Assessments for Verification of Flare
Criteria,30 and the Patient’s Assessment of
Arthritis Pain on a Visual Analog Scale
(Arthritis Pain VAS). The Patient’s, and the
Physician’s Global Assessments of Arthritis
Condition, and the Osteoarthritis Severity
Index (OSI) were also used.32
An OA flare was demonstrated in patients
discontinuing NSAID/analgesic therapy if
they had a baseline rating of fair, poor, or
very poor on both the Patient’s and the
Physician’s Global Assessments, and a
baseline Arthritis Pain VAS measurement of
at least 40 mm, on a scale where 0 = no pain,
and 100 mm is the most severe pain. Patients
with an OA flare also met at least two of the
following changes from the screening to the
baseline assessment: an increase in one or
more grades in the Patient’s Global
Assessment; an increase in one or more
grades in the Physician’s Global Assessment;
or an increase of at least one point on
the patient’s OSI functional capacity
classification scale. The scale for both the
Physician’s and Patient’s Global Assessments
ranged from 1 = very good condition
(asymptomatic) to 5 = very poor condition
(very severe symptoms). The OSI functional
capacity classification scale ranges from
469
0 to 24, where 0 = minimal pain and no
impairment of walking or other daily
activities, and 24 = severe pain and
disability.
Patients who did not receive prior OA
treatment, had a flare if they met three of the
following four criteria: an Arthritis Pain VAS
of at least 40 mm; an OSI score of at least
seven; a rating of poor or very poor on the
Patient’s Global Assessment; and a rating of
poor or very poor on the Physician’s Global
Assessment.
TREATMENT
Random assignment was stratified by site
in blocks of 10. Patients were assigned to one
of five treatment groups: placebo; or 100,
200, or 400 mg/day celecoxib; or naproxen
1000 mg/day administered in divided doses
(twice daily). Study medication was double-
masked, and patients were instructed to take
it with morning and evening meals.
Patients were permitted to take up to
325 mg aspirin daily, and up to 2 g
acetaminophen daily for up to 3 consecutive
days, when absolutely necessary for non-
arthritic conditions. However, the use of
acetaminophen was prohibited within 48
hours of an assessment of arthritis efficacy.
The use of oral or injectable corticosteroids
within 4 weeks of the first dose of study drug
was not permitted. Use of other medications
during the trial was permitted, but was
documented on the Concurrent Medications
Diary Card. Patients who completed the full
12 weeks of treatment were considered to
have completed the trial.
EFFICACY ASSESSMENT
Data for all measures of efficacy were
obtained at weeks 2, 6, and 12 (or at early
termination) after the first dose of study
medication, except for the WOMAC OA
Index questionnaire, which was
 AJ Kivitz, RW Moskowitz, E Woods et al.
Celecoxib for OA of the hip
administered during weeks 2 and 12.
Primary efficacy measures comprised of
improvements from baseline in the Patient’s
and Physician’s Global Assessments,
Arthritis Pain VAS, and the WOMAC OA
Index. The WOMAC OA Index is composed
of subscales that measure arthritis pain on a
scale of 0 – 20, where 0 = no pain and 20 =
worst pain; joint stiffness on a scale of 0 – 8,
where 0 = best functioning; physical
functioning on a scale of 0 – 68, where 0 =
best functioning; and a composite score from
0 to 96.32 The WOMAC OA Index was
disaggregated and the subscales were
analyzed separately.
Secondary measures of efficacy included
incidence of withdrawal due to lack of
arthritis efficacy and time to withdrawal due
to lack of arthritis efficacy.
SAFETY ASSESSMENT
Safety was assessed by recording treatment-
emergent adverse events and changes from
baseline in clinical laboratory tests, vital
signs, and physical examinations, all of
which were administered at visits on weeks 2,
6, and 12. Clinically relevant changes in
laboratory values were defined as: AST/ALT
≥ 3 × upper limit of normal (ULN), creatinine
≥ 1.3 × ULN, BUN ≥ 2 × ULN, hematocrit
decrease ≥ 5 percentage points from
baseline, and hemoglobin decrease ≥ 2 g/dl
from baseline.
STATISTICAL ANALYSIS
A sample size of 200 patients was considered
sufficient to detect a difference of 0.4, with a
power of at least 80% and a significance
level of 0.05, adjusted by Bonferroni’s
method33 for three celecoxib doses versus
placebo.
The demographic and baseline
characteristics of all randomly assigned
patients were assessed for homogeneity, with
470
treatment and site as factors, using the χ2-
test, two-way analysis of variance (ANOVA),
or the Cochran–Mantel–Haenzel (CMH) test,
as appropriate. Duration of OA was
categorized as less than 5 years or at least
5 years, and age was categorized as less than
65 years or at least 65 years.
All efficacy analyses were performed on
the intent-to-treat (ITT) cohort, which was
defined as all patients who were randomly
assigned and took one dose or more of study
medication. Missing data values were
assigned the patient’s most recent
observation for that outcome, including
those for patients with treatment failure.
Mean change analyses were performed
for all continuous efficacy variables using
analysis of covariance (ANCOVA) with
treatment and site as factors and the
corresponding baseline value as a covariate.
Linear trend tests, excluding the naproxen
group, and pair-wise comparisons among all
treatment groups were conducted.
For primary comparisons, the Hochberg
step-up procedure was used to control for type
I error associated with multiple treatment
group comparisons.34 To assess comparability
of efficacy among the treatment groups, the
Q-Ratio with a 95% confidence interval was
calculated by taking the ratio of the least
square mean changes for each celecoxib
treatment group versus naproxen. The effects
of age, gender, and disease duration were
also assessed for the efficacy variables.
Incidence of withdrawal due to treatment
failure was analyzed using Fisher’s exact test.
Overall and pairwise comparisons were
performed using the ITT cohort. Time to
withdrawal due to treatment failure was
calculated using the log-rank test, with
patients censored at the week 12 visit or at
withdrawal time. The safety analysis
included the ITT cohort. Adverse event
incidences were recorded and tabulated.
 AJ Kivitz, RW Moskowitz, E Woods et al.
Celecoxib for OA of the hip

Results treatment groups (P > 0.2; Table 1).

BASELINE CHARACTERISTICS OF
PATIENTS
A total of 1061 adult patients with OA of the
hip were enrolled in this randomized,
double-blind, multicenter study. There were
no clinically significant differences in
baseline demographics, vital signs, disease
duration, or disease severity among the
Consistent with the known epidemiology of
OA, approximately two-thirds of recruited
patients were female. Treatment groups were
comparable in terms of aspirin use (Table 1).
According to the Patient’s and the
Physician’s Global Assessments, the majority
(70 – 75%) of patients described their arthritis
condition as poor or very poor at baseline
(Table 1). There were no significant baseline

TABLE 1:
Patient demographic and baseline characteristicsa
Celecoxib
Placebo 100 mg/day 200 mg/day 400 mg/day Naproxen
Characteristic (n = 218) (n = 216) (n = 207) (n = 213) (n = 207) P-value
Mean age (range),
years 64 (30 – 85) 62 (28 – 93) 62 (30 – 86) 61 (28 – 88) 64 (32 – 87) 0.21
Female (%) 67 65 65 67 66 0.99
Weight, kg 83 (19) 84 (19) 83 (20) 83 (20) 84 (22) 0.99
Patients > 70 years
old (%) 33 30 30 25 36
Duration of disease,
years 7.9 7.3 7.2 6.9 7.3
Aspirin users (%) 22 15 18 18 16
Patient’s Global Assessment, %b,c 0.02
Fair 28 30 23 20 28
Poor 61 58 63 65 57
Very poor 12 11 14 15 14
Physician’s Global Assessment, %b,c 0.22
Fair 29 28 27 23 29
Poor 61 63 66 64 62
Very poor 9 8 7 13 9
Arthritis Pain
(VAS) 68.3 (14.9) 68.7 (16.5) 67.2 (17.0) 67.6 (15.7) 67.3 (16.5) 0.84
WOMAC Osteoarthritis Index
composite scoreb 50.7 (15.0) 49.3 (16.3) 50.2 (16.1) 50.9 (14.3) 49.8 (16.6) 0.75
Osteoarthritis Severity
Indexb 14.4 (3.3) 14.4 (3.4) 14.6 (3.4) 14.8 (3.2) 14.0 (3.5) 0.24
a
All data presented as mean (SD) unless otherwise indicated; WOMAC, Western Ontario and McMaster
universities.
b
Patient’s scale: 1 (very good) to 5 (very poor); Physician’s scale: 1 (very good) to 5 (very poor);
WOMAC Osteoarthritis scale: 0 – 96, lower score better; OSI scale: 0 – 24, lower score better.
c
Number of patients with ‘good’ Patient’s Global Assessment rating: one each in placebo, naproxen,
and celecoxib 200 mg/day and 400 mg/day groups; two in celecoxib 100 mg/day group; with ‘good’
Physician’s Assessment rating: two in celecoxib 100 mg/day and one in celecoxib 200 mg/day.

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Celecoxib for OA of the hip

differences in osteoarthritis severity among relevant. Similar proportions (P > 0.08) of

the groups, according to the Physician’s
Global Assessment, the WOMAC OA Index
and the OSI (P > 0.2). Although the
proportion of patients rating their baseline
arthritis severity as fair, poor or very poor
differed significantly among groups in the
Patient’s Global Assessment (P = 0.02), this
difference was not considered to be clinically
patients in each treatment group had a
history of GI bleeding (1 – 3%), gastro-
duodenal ulcers (9 – 18%) or NSAID GI
intolerance (10 – 15%).
Of the 1061 patients randomized, a total
of 538 (51%) completed this 12-week study
(Table 2). Fewer patients in the placebo
group (79 patients; 36%) completed the

TABLE 2:
Patient dispositiona and adverse eventsb
Celecoxib

Placebo 100 mg/day 200 mg/day 400 mg/day Naproxen

Characteristic (n = 218) (n = 216) (n = 207) (n = 213) (n = 207)
Patient disposition
Completed study 79 111 111 119 118
Lost to follow-up 2 4 0 2 1
Pre-existing violation 3 2 0 3 1
Protocol non-
compliance 5 6 8 9 7
Withdrawals due to
treatment failure 113 (52%) 76 (35%) 61 (29%) 55 (26%) 51 (25%)
Withdrawals due to
adverse events 16 (7%) 17 (8%) 27 (13%) 25 (12%) 29 (14%)
Total adverse events 123 (56%) 125 (58%) 136 (66%) 131 (62%) 131 (63%)
Gastrointestinal
adverse events 39 (18%) 36 (17%) 59 (29%) 63 (30%) 73 (35%)
Diarrhea 12 (6%) 8 (4%) 13 (6%) 21 (10%) 11 (5%)
Dyspepsia 16 (7%) 8 (4%) 18 (9%) 21 (10%) 19 (9%)
Nausea 5 (2%) 8 (4%) 12 (6%) 12 (6%) 12 (6%)
Abdominal pain 6 (3%) 8 (4%) 11 (5%) 10 (5%) 19 (9%)
Constipation 2 (< 1%) 1 (< 1%) 5 (2%) 4 (2%) 8 (4%)
Flatulence 3 (1%) 5 (2%) 5 (2%) 2 (< 1%) 12 (6%)
GI events causing
withdrawal 6 (3%) 6 (3%) 7 (3%) 11 (5%) 17 (8%)
Central nervous system
adverse events 50 (23%) 36 (17%) 52 (25%) 47 (22%) 31 (15%)
Headache 42 (19%) 26 (12%) 43 (21%) 34 (16%) 24 (12%)
Dizziness 5 (2%) 3 (1%) 4 (2%) 6 (3%) 2 (< 1%)
Peripheral edema 1 (< 1%) 3 (1%) 3 (1%) 11 (5%) 6 (3%)
Skin disorders
Rash 6 (3%) 8 (4%) 7 (3%) 4 (2%) 4 (2%)
Pruritus 4 (2%) 3 (1%) 3 (1%) 2 (< 1%) 1 (< 1%)
a
Mutually exclusive and exhaustive categories.
b
Only body system events affecting 3% or more of any treatment group, not including back pain, injury,
aggravated allergy, respiratory system disorders, or insomnia.

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Celecoxib for OA of the hip

study than in either of the celecoxib
100 mg/day (111 patients; 51%), 200 mg/day
(111 patients; 54%) or 400 mg/day (119
patients; 56%) groups, or the naproxen group
(118 patients; 57%). The main reasons for
study withdrawal were treatment failure (52%
placebo group; 25 – 35% active treatment
groups) and adverse events (7% placebo
group; 8 – 14% active treatment groups; Table
2). Only one patient failed to take at least one
dose of study medication.
EFFICACY
Patients treated with celecoxib 100 –
200 mg/day or naproxen experienced a
significant reduction in the severity of their
arthritis symptoms compared with those
receiving placebo, at all time points,
according to mean change analysis of the
Patient’s Global Assessment (Table 3;
P < 0.001). In addition, both mean change
and Q ratio analyses revealed that celecoxib
200 mg/day was comparable to naproxen
in improving the arthritis symptoms of
patients, at all time points. While
significantly more effective than placebo at
all time points, celecoxib 100 mg/day was
significantly less effective than celecoxib
200 mg/day and 400 mg/day at week 2 and
less effective than naproxen at weeks 2
and 12. The proportion of patients reporting
an improvement in arthritis condition from
baseline according to this efficacy measure
was also significantly greater for all
celecoxib treatment groups compared with
placebo at weeks 2, 6, and 12, (P ≤ 0.016;

TABLE 3:
Effect of treatment on symptoms of osteoarthritis. Patient’s and Physician’s Global
Assessments and Arthritis Pain VAS resultsa,b
Celecoxib
Placebo 100 mg/day 200 mg/day 400 mg/day Naproxen
Characteristic (n = 217) (n = 216) (n = 207) (n = 213) (n = 207)
Patient’s Global Assessmentc
2 weeks –0.6 –0.9e,f,g –1.2 –1.1 –1.2
6 weeks –0.6 –1.0 –1.1 –1.1 –1.1
12 weeks –0.5 –0.9e –1.1 –0.9h –1.1
Physician’s Global Assessmentc
2 weeks –0.6d –0.9 –1.1 –1.1 –1.1
6 weeks –0.6 –1.1 –1.1 –1.1 –1.1
12 weeks –0.6d –1.0 –1.0 –1.0 –1.1
Arthritis Pain VASc
2 weeks –11.8 –19.7e,f,g –24.4 –24.4 –26.5
6 weeks –13.2 –21.5 –25.1 –23.9 –24.8
12 weeks –11.1d –19.0f –23.3 –19.3 –22.3
aAll data presented as least square mean improvement.
bPatient’s scale: 1 (very good) to 5 (very poor); Physician’s scale: 1 (very good) to 5 (very poor), Arthritis Pain
VAS scale: 0 (no pain) to 100 mm (severe pain).
c
P < 0.001, all treatments versus placebo, except where indicated. Linear trend, excluding naproxen:
P < 0.001. Pairwise comparisons: naproxen versus celecoxib 100 mg/day, 200 mg/day, 400 mg/day not
statistically different, except where indicated.
d
P ≤ 0.05, celecoxib 100 mg/day versus placebo.
e
P ≤ 0.05, naproxen versus celecoxib 100 mg/day.
f
P ≤ 0.05, celecoxib 200 mg/day versus celecoxib 100 mg/day.
gP ≤ 0.05, celecoxib 400 mg/day versus celecoxib 100 mg/day.
hP ≤ 0.05, naproxen versus celecoxib 400 mg/day.

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 AJ Kivitz, RW Moskowitz, E Woods et al.
Celecoxib for OA of the hip
40
35
30
% improved patients
25
20
15
10
5
0
2 6
Weeks
FIGURE 1: Proportions of patients with improved arthritis condition according to the
Patient’s Global Assessment. aP ≤ 0.016 versus placebo at all time points. bP ≤ 0.044
versus celecoxib 100 mg/day at week 2
Fig. 1). At week 12, only 17% of
patients receiving placebo experienced an
improvement in their arthritis symptoms
compared with 26 – 34% of patients in
the active treatment groups. Significantly
more patients in the celecoxib 200 mg/day
and 400 mg/day groups reported an
improvement in arthritis condition than in
the celecoxib 100 mg/day group, at week 2
(P ≤ 0.044). The results of the Patient’s Global
Assessment also revealed that comparable
numbers of patients reported an
improvement in arthritis symptoms in the
celecoxib 200 mg/day and 400 mg/day
treatment groups at all time points. The
results of the Physician’s Global Assessment
were comparable to those of the Patient’s
Global Assessment (data not shown).
Compared with placebo, the mean
Arthritis Pain VAS scores were significantly
lower (improved) for patients treated with
celecoxib 100 – 400 mg/day (P ≤ 0.002) or
naproxen (P < 0.001). According to the mean
474
Placebo
Celecoxib 100 mg/daya
Celecoxib 200 mg/daya,b
Celecoxib 400 mg/daya,b
Naproxen 1000 mg/daya
12
scores, celecoxib 200 – 400 mg/day (P ≤ 0.04),
and naproxen (P = 0.003) provided signifi-
cantly greater pain relief than celecoxib
100 mg/day at week 2. Q-ratio analyses
confirmed that at all other time points
celecoxib 100 – 400 mg/day and naproxen
were equally effective.
According to the WOMAC OA composite
score, the symptoms of all active treatment
groups significantly improved (reduced
score) relative to the placebo group at
weeks 2 and 12 (P ≤ 0.014; Table 4). With
the exception of naproxen versus celecoxib
100 mg/day at week 12 (P ≤ 0.002), there
were no significant differences between
active treatments at any time point.
According to the WOMAC subscales, the
arthritis condition of all active treatment
groups improved (reduced score) signifi-
cantly relative to the placebo group at
weeks 2 and 12 (celecoxib 100 – 400 mg/day,
P ≤ 0.03; naproxen, P < 0.001; Fig. 2). At
week 2, the arthritis condition of patients
 AJ Kivitz, RW Moskowitz, E Woods et al.
Celecoxib for OA of the hip

TABLE 4:
Effect of treatment on symptoms of osteoarthritis. WOMAC OA index resultsa,b
Celecoxib
Placebo 100 mg/day 200 mg/day 400 mg/day Naproxen
Characteristic (n = 217) (n = 216) (n = 207) (n = 213) (n = 207)
WOMAC Osteoarthritis Composite scorec
Baseline score 50.7 49.3 50.2 50.9 49.8
2 weeks –3.4d –8.0 –11.7 –11.7 –12.7
12 weeks –4.6 –8.0e –10.3 –11.0 –12.4
a
All data presented as least square mean improvement. WOMAC, Western Ontario and McMaster universities.
b
WOMAC Osteoarthritis scale: 0 – 96, lower score better.
c
P < 0.001 all treatments versus placebo, except where indicated Linear trend, excluding naproxen:
P < 0.001. Pairwise comparisons: naproxen versus celecoxib 100 mg/day, 200 mg/day, 400 mg/day not
statistically different, except where indicated.
d
P = 0.014, celecoxib 100 mg/day versus placebo.
e
P ≤ 0.002, naproxen versus celecoxib 100 mg/day.

receiving celecoxib 200 mg/day was
significantly improved relative to those
receiving celecoxib 100 mg/day on all
WOMAC subscales (P ≤ 0.04). Patients
receiving celecoxib 400 mg/day also
experienced a significantly greater reduction
in WOMAC joint stiffness scores at week 2,
compared with those receiving celecoxib
100 mg/day (P = 0.03). At weeks 2 and 12,
naproxen scores were significantly lower than
celecoxib 100 mg/day for all WOMAC sub-
scales (P < 0.001). Celecoxib 200 – 400 mg/day
and naproxen had comparable treatment
effects, according to the WOMAC scores at
weeks 2 and 12 (Fig. 2).
In total, 356 patients withdrew from
the study due to a lack of treatment efficacy
(Table 2). Over half of the patients receiving
placebo withdrew (52%), compared with
25 – 35%, of those receiving active treatments.
Compared with placebo, this difference was
significant for each active treatment group
(P ≤ 0.001). Patients withdrew at a significantly
higher rate in the celecoxib 100 mg/day
group compared with patients in the celecoxib
400 mg/day (P = 0.04) or naproxen (P = 0.02)
treatment groups.
The time to withdrawal due to lack of
arthritis efficacy or adverse events was
significantly longer for all active treatment
groups compared with placebo (P < 0.001), but
comparable among all active treatment groups.
SAFETY AND TOLERABILITY
The incidence of adverse events, which were
reported by 646 (61%) of the 1060 patients
receiving at least one dose of study
medication, was 56% in the placebo group
and 58 – 66% in the active treatment groups
(Table 2). Although the incidence of
withdrawals (114 in total) due to adverse
events was greater in the active treatment
groups (8 – 14%) than in the placebo group
(7%), this difference was not significant
(P = 0.083).
Of the adverse events occurring in at least
5% of patients, headache was most
frequently reported, while GI-related adverse
events comprised five of the nine most
commonly reported adverse events (Table 2).
GI-related adverse events were reported by
270 patients, and were mostly mild to
moderate in severity. The incidence of GI-
related adverse events was 35% in the
naproxen group, 17 – 30% in the celecoxib
100 – 400 mg/day groups, and 18% in
the placebo group, with patients often
experiencing multiple symptoms. The

475
 AJ Kivitz, RW Moskowitz, E Woods et al.
Celecoxib for OA of the hip

A
12 Pain

11
Mean score

10 Placebo
Celecoxib 100 mg/daya
Celecoxib 200 mg/daya,c
9
Celecoxib 400 mg/daya
Naproxen 1000 mg/dayb,d
8

7
0 2 12
Weeks
aP< 0.03 or bP < 0.001 versus placebo at weeks 2 and 12. cP < 0.04 versus celecoxib
100 mg/day at week 2. dP < 0.002 versus celecoxib 100 mg/day at weeks 2 and 12.

B
5 Joint stiffness
Placebo
Celecoxib 100 mg/daya
Mean score

Celecoxib 200 mg/daya

4.5
Celecoxib 400 mg/daya,c
Naproxen 1000 mg/dayb,d

3.5
0 2 12
Weeks
aP
< 0.03 or bP < 0.001 versus placebo at weeks 2 and 12. cP < 0.03 versus celecoxib
100 mg/day at week 2. dP < 0.002 versus celecoxib 100 mg/day at weeks 2 and 12.

C
40 Physical functioning
Placebo
Celecoxib 100 mg/daya
35
Celecoxib 200 mg/daya,c
Mean score

Celecoxib 400 mg/daya

30 Naproxen 1000 mg/dayb,d

25

20
0 2 12
Weeks
aP < 0.03 or bP < 0.001 versus placebo at weeks 2 and 12. cP < 0.04 versus celecoxib

100 mg/day at week 2. dP < 0.002 versus celecoxib 100 mg/day at weeks 2 and 12.
FIGURE 2: WOMAC Osteoarthritis Index mean scores. Bars represent standard error of
the mean

476
 AJ Kivitz, RW Moskowitz, E Woods et al.
Celecoxib for OA of the hip
incidence of GI-related adverse events
causing withdrawal was 8% in the naproxen
group, 5% in the celecoxib 400 mg/day
group, and 3% in the placebo or celecoxib
100 – 200 mg/day groups. Three patients
experienced serious GI-related adverse
events, one from the naproxen group, who
had a history of low-dose aspirin use,
(clinically significant duodenal ulcer
hemorrhage and endoscopic lesion
accompanied by melena), and one from the
placebo (bleeding hemorrhoids) and
celecoxib 100 mg/day (gastroesophageal
reflux) groups, respectively. There were no
clinically significant hematologic adverse
events or changes in vital signs or weight
from baseline to week 12 or early
termination in any group. There was no
clinically significant difference in the
incidence of edema between the celecoxib
and naproxen treatment groups. The
incidence of aggravated hypertension, renal
events, and hepatic events in each treatment
group was low (≤ 1%), with none leading to
withdrawal.
Discussion
The results of this large, randomized, double-
blind, placebo controlled trial demonstrate
the clinical efficacy and safety of therapeutic
and supratherapeutic dosages of the COX-1
sparing, COX-2 specific inhibitor, celecoxib
in patients with OA of the hip. Treatment
with celecoxib 200 – 400 mg/day over a
12-week period was associated with
a sustained reduction in the symptoms of
OA, that was comparable to a standard
therapeutic dose of the conventional NSAID,
naproxen. Furthermore, all celecoxib doses
tended to be tolerated as well as or better
than naproxen.
For all measures of efficacy (Patient’s and
Physician’s Global Assessments, Arthritis
Pain VAS, and the WOMAC OA index), each
477
active treatment group significantly
improved the symptoms of arthritis
compared with placebo, at each time point.
Celecoxib 200 – 400 mg/day and naproxen
were comparable in efficacy, while
significantly more effective than celecoxib
100 mg/day for Patient’s Global Assessment,
Arthritis Pain (VAS) and WOMAC OA
composite score at certain time points. This
may indicate that celecoxib 100 mg/day
is a submaximally effective dose for the
treatment of OA, a trend that has also been
observed in a pooled analysis of three OA
studies of the hip and knee (data on file –
Pharmacia Corporation, Peapack, NJ, USA).
The WOMAC subscale for pain results
demonstrated that celecoxib 100 –
400 mg/day, and naproxen, provided
patients with a significant level of pain relief
relative to placebo. Celecoxib doses of 200
and 400 mg/day were similarly efficacious
and comparable to naproxen.
The overall incidence of adverse events
in patients receiving celecoxib 100 –
400 mg/day or naproxen 1000 mg/day was
comparable, and similar to those receiving
placebo. There was no significant difference
among the active treatment and placebo
groups in the incidence of adverse events
causing withdrawal. The incidence of GI
adverse events and of withdrawals due to GI
adverse events in the naproxen group was
generally comparable to or higher than the
celecoxib 100 – 400 mg/day groups. One
patient, in the naproxen group, experienced
a serious, clinically significant ulcer
complication (duodenal ulcer hemorrhage).
The incidence of aggravated hypertension,
hepatic, and renal adverse events was low in
all treatment groups, with none leading to
withdrawal.
These efficacy and safety results for OA of
the hip are comparable to those of a recently
published celecoxib efficacy study of similar
 AJ Kivitz, RW Moskowitz, E Woods et al.
Celecoxib for OA of the hip
design and size, in patients with OA of the
knee.24 This study also confirms published
reports of the efficacy of celecoxib 200 mg/day
in patients with OA of the knee.23 The present
results also reinforce the findings of published
studies demonstrating the comparable
efficacy of celecoxib, and the conventional
NSAIDs diclofenac34 and naproxen35 in the
management of OA inflammation and pain.
The efficacy data from these studies suggest
that celecoxib is therapeutically equivalent to
conventional NSAIDs.
The current study is further supportive of
the general safety of celecoxib relative to
conventional NSAIDs. Numerous previous
studies have established the superior GI
safety profile of celecoxib compared with
conventional NSAIDs.26,36,37 Furthermore,
celecoxib also demonstrates promising renal
• Received for publication 17 September 2001 • Accepted 27 September 2001
©2001 Cambridge Medical Publications
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Address for correspondence
AJ Kivitz, MD
Altoona Center for Clinical Research, 1125 Old Route 220 North Duncansville,
Altoona, PA 16635-0909, USA.
E-mail: akivitz@prodigy.net
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