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Efficacy and safety of four doses of lumiracoxib versus diclofenac in patients with knee or hip primary osteoarthritisA phase II four-week multicenter randomized double-blind placebo-controlled trial.

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Arthritis & Rheumatism (Arthritis Care & Research)
Vol. 51, No. 4, August 15, 2004, pp 549 –557
DOI 10.1002/art.20525
© 2004, American College of Rheumatology
ORIGINAL ARTICLE
Efficacy and Safety of Four Doses of Lumiracoxib
Versus Diclofenac in Patients With Knee or Hip
Primary Osteoarthritis: A Phase II, Four-Week,
Multicenter, Randomized, Double-Blind,
Placebo-Controlled Trial
THOMAS J. SCHNITZER,1 JANNIE BEIER,2 PIET GEUSENS,3 PAUL HASLER,4 SANJAY K. PATEL,5
INGO SENFTLEBER,6 XAVIER GITTON,7 ALAN MOORE,7 VICTOR S. SLOAN,8 AND GYULA POÓR9
Objective. To compare the efficacy and tolerability of the novel cyclooxygenase 2-selective inhibitor lumiracoxib with
placebo and diclofenac in osteoarthritis (OA).
Methods. Adults (n ⴝ 583) with knee or hip OA were randomized to receive for 4 weeks lumiracoxib 50, 100, or 200 mg
twice daily or 400 mg once daily; placebo; or diclofenac 75 mg twice daily. Efficacy assessments included overall joint
pain intensity and Western Ontario and McMaster Universities Osteoarthritis Index subscales; tolerability was evaluated
by adverse event and physician reporting.
Results. All lumiracoxib doses were superior to placebo in relieving pain, improving stiffness, and improving physical
function after 4 weeks. At study endpoint, pain relief was comparable among all lumiracoxib dosages and similar to
diclofenac. Lumiracoxib tolerability was superior to diclofenac and comparable to placebo.
Conclusion. Lumiracoxib provides predictable and sustained relief from pain, stiffness, and impaired physical function
in OA. Lumiracoxib shows clinically comparable efficacy and superior tolerability to diclofenac.
KEY WORDS. Lumiracoxib; Diclofenac; Pain relief; Osteoarthritis.
INTRODUCTION
Osteoarthritis (OA) is not only the most common musculoskeletal disorder, affecting approximately 10% of the
population worldwide and 16 –30 million people in the
US (1– 4), but more importantly is a leading cause of pain,
1
Thomas J. Schnitzer, MD: Northwestern University Feinberg School of Medicine, Chicago, Illinois; 2Jannie Beier,
MD: Private Rheumatology Practice, Odense, Denmark;
3
Piet Geusens, MD: Limburgs University, Diepenbeek, Belgium; 4Paul Hasler, MD: Felix Platter Spital, Basel, Switzerland; 5Sanjay K. Patel, MD: Adan House Surgery, Durham,
United Kingdom; 6Ingo Senftleber, MD: Grabenbachstrasse
12, Messkirch, Germany; 7Xavier Gitton, MD, Alan Moore,
MD: Novartis Pharma AG, Basel, Switzerland; 8Victor S.
Sloan, MD: Novartis Pharmaceuticals Corporation, East
Hanover, New Jersey; 9Gyula Poór, MD: National Institute of
Rheumatology, Budapest, Hungary.
Address correspondence to Thomas J. Schnitzer, MD,
Northwestern Center for Clinical Research, 710 North Lake
Shore Drive, Room 1020, Chicago, IL 60611. E-mail:
tjs@northwestern.edu.
Submitted for publication January 31, 2003; accepted in
revised form September 14, 2003.
loss of physical function, and reduction in health-related
quality of life (5). Treatment of this condition begins with
a foundation of patient education, exercise, optimization
of weight, and social support to which pharmacologic
management is added, as needed, to control pain and
increase physical function (6 – 8). Despite having inferior
efficacy to nonsteroidal antiinflammatory drugs (NSAIDs)
(9,10), acetaminophen has been proposed as the initial
therapeutic agent in OA function (6 – 8). These recommendations are based largely on the superior safety and tolerability profile of acetaminophen compared with traditional NSAIDs.
The major serious side effect of traditional NSAIDs is
gastrointestinal (GI) toxicity, manifest as peptic ulcers,
perforations, or bleeding (11,12). Occurring at an annualized rate of 2– 4% in patients regularly taking full prescription doses, these events are a consequence of a reduction
in prostaglandin synthesis due to inhibition of the cyclooxygenase (COX) pathway by NSAIDs (13). The discovery
of a second COX isoenzyme (COX-2) and the subsequent
knowledge of its tissue distribution, regulation, expression, and function led to the COX-2 hypothesis: specific
549
550
inhibitors of COX-2 will provide equivalent efficacy to
traditional NSAIDs (which inhibit both COX-1 and COX-2
isoenzymes) but will result in greater GI safety (14).
This hypothesis was formally tested by the development
of COX-2–selective inhibitors and subsequent clinical investigations of these drugs. Results of trials with currently
marketed COX-2–selective inhibitors have demonstrated
an efficacy profile that is similar to traditional NSAIDs
with superior GI safety, measured as fewer endoscopic GI
ulcers and better GI tolerability (15–28). Large GI outcome
studies with 2 COX-2–selective inhibitors, rofecoxib and
celecoxib, have generally supported these findings but
have generated additional questions regarding the longterm cardiovascular and GI safety of these agents (19,25,
29,30).
Lumiracoxib is a novel COX-2–selective inhibitor chemically distinct from the other COX-2–selective inhibitors
by virtue of the absence of a sulfur-containing moiety and
the presence of a carboxylic acid group, making it a weakly
acidic molecule (pKa 4.7) (31). Previous studies have demonstrated the efficacy of lumiracoxib in acute dental pain
(32,33), but this phase II dose-ranging study is the first
assessment of lumiracoxib in patients with OA.
The primary goal of this study was to evaluate the efficacy of different dosages and dosing regimens of lumiracoxib compared with both placebo and the maximum recommended therapeutic dosage (75 mg twice daily) of
diclofenac.
METHODS
This was an international, randomized, double-blind, double-dummy, placebo-controlled, parallel-group, multicenter study conducted over 4 weeks. The primary objective was to determine the efficacy of lumiracoxib at 4
dosages, compared with placebo, in the treatment of OA as
evaluated by the change in overall pain intensity in the
most severely affected joint. Secondary objectives included the assessment of the safety and tolerability profile
of lumiracoxib compared with placebo, and the efficacy,
safety, and tolerability compared with the maximum therapeutic dosage of diclofenac (75 mg twice daily).
The study was conducted at 50 centers in 7 countries
(Belgium, Denmark, Germany, Hungary, Switzerland, UK,
and US) between August and December 1999. The study
was approved by the appropriate institutional review
boards and was conducted according to Good Clinical
Practice guidelines and in accordance with the Declaration
of Helsinki (1964 and subsequent revisions). Patients provided written informed consent prior to any study procedure.
Patients. Adult patients (aged 18 –75 years) were eligible to participate in the study if they had a clinical or
radiographic diagnosis of primary OA of the knee or hip
(diagnosed according to the American College of Rheumatology criteria) (34,35), had been symptomatic for at least 3
months prior to enrollment, and had received an NSAID or
other analgesic therapy on a regular basis. Patients were
required to have experienced a pain intensity of at least 40
Schnitzer et al
mm on a 100-mm visual analog scale (VAS; 0 mm representing no pain and 100 mm representing very severe
pain) in the most severely affected joint during the 24
hours prior to randomization. Patients were excluded from
the trial if they had secondary OA or had a history of, or
evidence of, specified confounding disorders (e.g., septic
arthritis, inflammatory joint disease, gout, Paget’s disease,
or articular fracture). Significant medical problems that
would, in the opinion of the investigator, influence outcomes were also grounds for exclusion, as were a history of
GI bleeding; open knee or hip surgery within 1 year prior
to study entry; anemia; or hepatic, renal, or blood coagulation disorders. Women who were pregnant, lactating, or
who were not using adequate birth control (and were of
childbearing age) were not eligible. Potentially confounding concomitant treatment, including physiotherapy, any
NSAID, systemic corticosteroids, intraarticular injection
into the study joint, chondroitin sulfate, glucosamine sulfate, diacerhein, minocycline, H2 blockers, proton-pump
inhibitors, misoprostol, or antacids, were not permitted
during the study period.
After a washout period of 3–7 days, during which no
NSAID therapy was permitted, eligible patients were randomized to receive lumiracoxib 50 mg twice daily, 100 mg
twice daily, 200 mg twice daily, 400 mg once daily, diclofenac 75 mg twice daily, or placebo. Patients were permitted a maximum of 6 tablets (total dose 3 gm) of acetaminophen per day as rescue medication. Compliance
with study treatment and the use of rescue medication
were assessed through direct questioning and capsule/
tablet counting.
Variables. The primary efficacy comparison was between placebo and each active arm at week 4 of the overall
joint pain intensity experienced in the most severely affected joint (hip or knee) over the previous 24 hours, using
a 100-mm VAS. Overall joint pain intensity was assessed
by asking subjects: “Please indicate with a vertical mark
through the horizontal line the most pain you had from
your OA joint over the last 24 hours.” The joint assessed to
be the most severely affected at screening was evaluated
for the entire study.
Secondary efficacy measures were overall joint (for the
most severely affected joint) pain intensity according to
the 100-mm VAS by visit (i.e., at weeks 1 and 2); patient’s
and physician’s global assessment of disease activity using
100-mm VAS; assessment of pain, stiffness, and physical
function using the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC 3.1 Likert questionnaire) (36); and evaluation of functional impairment using
the Health Assessment Questionnaire (HAQ) standard
disability index. The global assessment of disease activity,
the HAQ, and the WOMAC were applied at baseline and
week 4.
Safety variables included adverse events (AEs), serious
AEs (SAEs), laboratory evaluations, vital signs, and physical examinations including a specific assessment of peripheral edema conducted each week. AEs were graded
based on qualitative assessment of the extent or intensity
of the AE by the investigator, or as reported by the subject.
Lumiracoxib Versus Diclofenac in Osteoarthritis
551
Figure 1. Disposition of study participants. bid ⫽ twice daily; qd ⫽ once daily; AEs ⫽ adverse events.
SAEs were defined as any event that was fatal or considered life-threatening, which required prolonged hospitalization; caused permanent disability; or constituted cancer, congenital anomaly, or overdose.
Statistical analyses. The sample size was calculated to
detect an 11-mm difference between lumiracoxib and placebo for pain assessed on the VAS after 4 weeks of treatment, assuming a 20-mm SD and a dropout rate of 10%. A
sample size of 85 patients per treatment group was required to ensure 80% power at a significance level of 5%
(two-sided) on the basis of these assumptions.
Descriptive statistics were used for baseline demographics and background data. Homogeneity between treatment
groups at baseline was assessed using a one-way analysis
of variance F-test for continuous variables and a chi-square
test for categorical variables.
The efficacy analyses were performed using a modified
intent-to-treat (ITT) population, comprising all patients
who were randomized to treatment, who had received 1 or
more doses of trial medication, and for whom at least 1
postbaseline assessment was obtained. A postbaseline, last
observation carried forward approach was used to account
for any missing data points, thus, baseline data were not
carried forward if postbaseline data were not available. All
patients who were randomized and had received at least 1
dose of study medication were included in the safety evaluation.
The confirmatory analysis was performed on the ITT
population to determine the minimum effective regimen
that reached statistical significance. The closed version of
the multiple union intersection procedure of the Dunnett
test according to Marcus and colleagues (37,38) was used
to compare the lumiracoxib regimens with placebo with
respect to the primary efficacy variable. The least-squares
means were obtained using an analysis of variance model,
which considered change from baseline in overall joint
pain intensity as the response variable, with treatment and
center as factors.
The secondary analyses included an analysis of covariance to compare treatment groups with respect to primary
and secondary efficacy variables, with treatment and center as factors and the overall joint pain intensity at baseline
as a covariate. All pairwise comparisons were performed
at the level of 5% (two-sided) without adjusting for multiple comparisons.
The assessment of safety was based upon the frequency
of AEs, electrocardiogram results, vital signs, and on the
consideration of notable laboratory values that fell outside
predetermined ranges (e.g., doubling of creatinine levels or
increase in creatinine ⬎2 mg/ml, increase in liver transaminase levels to ⬎3 times the upper limit of normal, anemia
defined as a ⱖ2 gm/dl reduction in hemoglobin from baseline).
RESULTS
Study population. A total of 583 patients were randomized (Figure 1) to receive either lumiracoxib 50 mg twice
daily (n ⫽ 98), 100 mg twice daily (n ⫽ 96), 200 mg twice
daily (n ⫽ 99), 400 mg once daily (n ⫽ 99), diclofenac 75
mg twice daily (n ⫽ 94), or placebo (n ⫽ 97). The treatment
groups were well matched with no significant differences
in baseline demographics and disease characteristics (Table 1). In total, 65 (11%) patients discontinued treatment
552
Schnitzer et al
Table 1. Patient characteristics*
No. of patients
Age, mean ⫾ SD years
Sex, no. (%)
Male
Female
BMI, mean ⫾ SD kg/m2
Disease duration, mean
(range) years
Lumiracoxib
50 mg bid
Lumiracoxib
100 mg bid
Lumiracoxib
200 mg bid
Lumiracoxib
400 mg qd
Diclofenac
75 mg bid
Placebo
Total
98
61.3 ⫾ 8.5
96
59.8 ⫾ 9.4
99
59.5 ⫾ 9.9
99
60.1 ⫾ 9.4
94
59.7 ⫾ 8.6
97
61.5 ⫾ 9.3
583
60.3 ⫾ 9.2
31 (32)
67 (68)
30.0 ⫾ 6.9
7.4 (0–45)
29 (30)
67 (70)
29.7 ⫾ 5.6
6.6 (0–30)
25 (25)
74 (75)
29.7 ⫾ 6.6
6.9 (0–51)
41 (41)
58 (59)
30.3 ⫾ 5.0
6.3 (0–29)
30 (32)
64 (68)
30.1 ⫾ 7.5
6.3 (0–36)
32 (33)
65 (67)
29.2 ⫾ 5.9
8.0 (0–55)
188 (32)
395 (68)
29.8 ⫾ 6.3
6.9 (0–55)
* bid ⫽ twice daily; qd ⫽ once daily; BMI ⫽ body mass index.
prior to the end of the study. The main reasons for withdrawal were the emergence of AEs (n ⫽ 32), lack of efficacy
(n ⫽ 10; with 6 in the placebo group), protocol violations
(n ⫽ 9), and withdrawal of consent (n ⫽ 8). The mean
exposure to study treatment in the 6 groups ranged from 26
to 28 days.
The greatest percentage of patients taking rescue medication (68%) and the greatest use of rescue medication
(mean of 1.1 tablets per day) were found in the placebo
group. Between 48% and 60% of patients in the active
treatment groups took rescue medication (mean of 0.4 to
0.6 tablets per day). No significant differences were seen
between any of the active treatment groups.
Overall joint pain intensity. All doses of lumiracoxib
were found to be effective in the confirmatory analysis of
the primary efficacy variable: overall joint pain intensity.
All were superior to placebo (P ⱕ 0.002) in terms of change
from baseline from week 1 onward until study end (Figure
2). Mean overall joint pain intensity VAS scores at baseline
of 64.7– 67.0 mm were reduced to 33.7–38.4 mm at week 4
with active treatment (all dosages of lumiracoxib and diclofenac) and from 67.9 mm to 50.2 mm with placebo.
Thus, all doses of lumiracoxib showed significantly lower
joint pain intensity at 4 weeks compared with placebo,
with a somewhat greater mean change for the lumiracoxib
400 mg once daily group. Throughout the study, there
were no significant differences in the degree of reduction
of pain intensity between any of the 3 lumiracoxib doses
administered twice daily compared with the 400 mg once
daily dose, except for a modestly reduced effect for the
50 mg twice daily and 100 mg twice daily doses at week 1
Figure 2. Overall pain intensity measured using a 100-mm visual analog scale (VAS) in adult patients with primary osteoarthritis of the
knee or hip who were randomized to receive lumiracoxib 50 mg twice daily (bid), 100 mg twice daily, 200 mg twice daily, 400 mg once
daily (qd); or diclofenac 75 mg twice daily; or placebo for 4 weeks. P values were calculated on the least square means. **P ⫽ 0.002,
lumiracoxib 50 mg twice daily versus placebo. ***P ⱕ 0.001, lumiracoxib 50 mg twice daily versus placebo. #P ⱕ 0.001, lumiracoxib
100 mg twice daily, 200 mg twice daily, and 400 mg once daily versus placebo. †P ⬍ 0.001, diclofenac 75 mg twice daily versus placebo.
Lumiracoxib Versus Diclofenac in Osteoarthritis
553
Table 2. Patient’s and physician’s global assessments of disease activity at baseline and week 4*
Patient’s global assessment of disease
activity (VAS mm), mean ⴞ SD
Physician’s global assessment of disease
activity (VAS mm), mean ⴞ SD
Treatment group
No.
Baseline
Week 4
No.
Baseline
Week 4
Lumiracoxib 50 mg bid
Lumiracoxib 100 mg bid
Lumiracoxib 200 mg bid
Lumiracoxib 400 mg qd
Diclofenac 75 mg bid
Placebo
95
94
92
98
92
96
63.1 ⫾ 17.5
62.0 ⫾ 18.5
64.0 ⫾ 17.3
63.7 ⫾ 16.5
62.2 ⫾ 16.2
62.5 ⫾ 18.1
38.8 ⫾ 21.5
37.8 ⫾ 22.2
37.5 ⫾ 24.0
35.6 ⫾ 24.1
34.4 ⫾ 23.0
50.0 ⫾ 23.0
94
94
91
96
92
95
59.1 ⫾ 15.7
56.6 ⫾ 17.1
61.3 ⫾ 14.7
59.6 ⫾ 15.1
57.2 ⫾ 15.6
60.4 ⫾ 15.7
37.3 ⫾ 20.2
33.4 ⫾ 20.4
34.3 ⫾ 20.0
33.1 ⫾ 21.3
33.4 ⫾ 18.5
47.3 ⫾ 22.1
* VAS ⫽ visual analog scale; bid ⫽ twice daily; qd ⫽ once daily.
only (P ⬍ 0.05). At the study end, all dosages of lumiracoxib demonstrated comparable efficacy to each other and
to diclofenac 75 mg twice daily.
Global assessment of disease activity. For the secondary endpoint, physician’s global assessment of disease activity, all of the active treatments (lumiracoxib and diclofenac) were significantly superior to placebo at week 4 (all
P ⱕ 0.001) (Table 2). Moreover, after 4 weeks of treatment,
the results with each of the lumiracoxib dosages studied
were similar to diclofenac 75 mg twice daily. Mean physician global assessment VAS scores at baseline of 56.6 –
61.3 mm were reduced to 33.1–37.3 mm at week 4 with
active treatment (all dosages of lumiracoxib and diclofenac) and from 60.4 mm to 47.3 mm with placebo. Similarly, all active treatments (all dosages of lumiracoxib and
diclofenac) were significantly superior to placebo at week
4 for the patient’s global assessment (all P ⱕ 0.001) (Table
2); active treatments reduced mean VAS baseline scores of
62.0 – 64.0 mm to 34.4 –38.8 mm by week 4, whereas patients receiving placebo had a reduction from 62.5 mm at
baseline to 50.0 mm at week 4.
WOMAC assessments. The 3 WOMAC subscales were
assessed as secondary efficacy measures (Table 3). The
WOMAC pain subscale score demonstrated that all lumiracoxib treatment regimens were as effective as diclofenac
75 mg twice daily. At week 4, all active treatment groups
were statistically superior to placebo (mean score 8.1; P ⱕ
0.001 for lumiracoxib 50 mg twice daily [mean score 6.4],
lumiracoxib 200 mg twice daily [mean score 6.4], lumira-
coxib 400 mg once daily [mean score 5.7], and diclofenac
75 mg twice daily [mean score 6.2]; P ⫽ 0.006 for lumiracoxib 100 mg twice daily [mean score 6.8]).
On the WOMAC physical function subscale, all active
treatment groups, with the exception of lumiracoxib 100
mg twice daily, achieved statistically superior results at
week 4 compared with placebo (mean score 27.3; P ⱕ
0.001, [mean scores 19.0 –21.5]; P ⫽ 0.056 for lumiracoxib
100 mg twice daily [mean score 23.2]).
On the WOMAC stiffness subscale, the scores for all
lumiracoxib dosages were similar to diclofenac. All active
treatments achieved statistically superior scores compared
with placebo (mean 3.5) at week 4 (P ⱕ 0.001 for lumiracoxib 50 mg twice daily, 200 mg twice daily, and 400 mg
once daily; P ⫽ 0.035 for lumiracoxib 100 mg twice daily;
P ⫽ 0.002 for diclofenac 75 mg twice daily). The mean
score at week 4 was 2.7 for all active treatments except
lumiracoxib 100 mg twice daily (mean score 3.0).
Overall, the effects of the various dosages of lumiracoxib
on all WOMAC scores at week 4 were similar.
Health Assessment Questionnaire. Significant differences in the HAQ score were observed for the lumiracoxib
50 mg twice daily (mean score 0.8; P ⫽ 0.007), lumiracoxib
200 mg twice daily (mean score 0.8; P ⫽ 0.008), lumiracoxib 400 mg once daily (mean score 0.7; P ⫽ 0.009), and
diclofenac 75 mg twice daily (mean score 0.7; P ⫽ 0.001)
groups compared with placebo (mean score 1.0) after 4
weeks of treatment. Although the HAQ score for the 100
mg twice daily group improved over the course of the
study, at week 4 the comparison with placebo was not
Table 3. WOMAC subscale scores at baseline and week 4*
WOMAC pain,
mean ⴞ SD
WOMAC physical function,
mean ⴞ SD
WOMAC stiffness,
mean ⴞ SD
Treatment group
No.
Baseline
No.
Week 4
No.
Baseline
No.
Week 4
No.
Baseline
No.
Week 4
Lumiracoxib 50 mg bid
Lumiracoxib 100 mg bid
Lumiracoxib 200 mg bid
Lumiracoxib 400 mg qd
Diclofenac 75 mg bid
Placebo
96
95
96
97
94
95
9.8 ⫾ 3.6
9.6 ⫾ 3.0
9.6 ⫾ 3.7
9.5 ⫾ 3.3
9.5 ⫾ 3.4
9.6 ⫾ 3.5
95
94
92
97
92
93
6.4 ⫾ 4.1
6.8 ⫾ 3.9
6.4 ⫾ 4.0
5.7 ⫾ 3.9
6.2 ⫾ 4.0
8.1 ⫾ 3.6
96
94
95
98
93
95
31.8 ⫾ 12.1
31.1 ⫾ 11.3
31.5 ⫾ 11.8
32.0 ⫾ 11.2
31.1 ⫾ 12.6
32.7 ⫾ 10.4
96
93
91
97
90
94
21.5 ⫾ 13.7
23.2 ⫾ 13.0
20.8 ⫾ 14.1
19.0 ⫾ 12.8
20.0 ⫾ 13.2
27.3 ⫾ 12.7
96
94
92
98
91
92
4.4 ⫾ 1.6
4.3 ⫾ 1.6
4.2 ⫾ 1.6
4.3 ⫾ 1.7
4.0 ⫾ 1.5
4.2 ⫾ 1.5
96
94
92
98
91
93
2.7 ⫾ 1.7
3.0 ⫾ 1.8
2.7 ⫾ 1.8
2.7 ⫾ 1.9
2.7 ⫾ 1.8
3.5 ⫾ 1.8
* WOMAC ⫽ Western Ontario and McMaster Universities Osteoarthritis Index; bid ⫽ twice daily; qd ⫽ once daily.
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Schnitzer et al
Table 4. Most frequent adverse events (>5% for any group)*
Adverse event
Gastrointestinal disorders
Abdominal pain†
Diarrhea
Nausea
Constipation
Dyspepsia
Abdominal distension
Cardiac disorders
Edema‡
Nervous system disorders
Headache
Dizziness (excluding
vertigo)
Fatigue
Infections and infestations
Nasopharyngitis
Lumiracoxib
50 mg bid
n ⴝ 98
no. (%)
Lumiracoxib
100 mg bid
n ⴝ 96
no. (%)
Lumiracoxib
200 mg bid
n ⴝ 99
no. (%)
Lumiracoxib
400 mg qd
n ⴝ 99
no. (%)
Diclofenac
75 mg bid
n ⴝ 94
no. (%)
Placebo
n ⴝ 97
no. (%)
4 (4.1)
8 (8.2)
4 (4.1)
5 (5.1)
6 (6.1)
3 (3.1)
6 (6.3)
2 (2.1)
8 (8.3)
3 (3.1)
4 (4.2)
3 (3.1)
7 (7.1)
6 (6.1)
4 (4.0)
1 (1.0)
3 (3.0)
2 (2.0)
6 (6.1)
10 (10.1)
1 (1.0)
5 (5.1)
2 (2.0)
0 (0.0)
14 (14.9)
10 (10.6)
10 (10.6)
6 (6.4)
6 (6.4)
5 (5.3)
6 (6.2)
4 (4.1)
1 (1.0)
2 (2.1)
2 (2.1)
2 (2.1)
5 (5.1)
11 (11.5)
8 (8.1)
8 (8.1)
5 (5.3)
4 (4.1)
4 (4.1)
2 (2.0)
7 (7.3)
4 (4.2)
5 (5.1)
5 (5.1)
2 (2.0)
2 (2.0)
5 (5.3)
1 (1.1)
9 (9.3)
1 (1.0)
0 (0.0)
5 (5.2)
2 (2.0)
1 (1.0)
2 (2.1)
1 (1.0)
1 (1.0)
3 (3.1)
3 (3.0)
3 (3.0)
5 (5.3)
2 (2.1)
* bid ⫽ twice daily; qd ⫽ once daily; excl. ⫽ excluding.
† With one exception, which occurred in the placebo group, this includes upper abdominal pain only.
‡ Although not always specified, it can be assumed that all patients had peripheral/lower limb edema.
significant (mean score 0.9; P ⫽ 0.177). No statistically
significant differences were seen either between the different lumiracoxib treatment groups or between any lumiracoxib dosage and diclofenac.
Safety and tolerability. The majority of AEs reported
were mild to moderate in intensity in all treatment groups.
The incidence of any AE (i.e., including mild to severe,
treatment related, and nontreatment related) was similar
across the 4 lumiracoxib dosage groups and the placebo
group (Table 4). No dosage-related trend was observed in
the incidence of AEs overall, or in moderate to severe AEs.
The most frequently reported treatment-related AEs across
all treatment groups (including placebo and diclofenac)
were diarrhea, nausea, dyspepsia, and edema. The proportion of patients experiencing at least 1 GI-related AE was
markedly higher among patients treated with diclofenac
75 mg twice daily (41.5%) compared with placebo (17.5%)
and each lumiracoxib group (23.2–26.5%). Moreover, the
incidence of moderate to severe GI AEs was greater in
patients treated with diclofenac 75 mg twice daily than
with all lumiracoxib groups combined (for diclofenac,
lumiracoxib all doses, and placebo, respectively: abdominal pain, 9%, 2%, and 3%; nausea, 5%, 1%, and 1%;
dyspepsia, 3%, 2%, and 1%). Edema was generally mild in
degree and reported with an incidence ranging from 4.1%
in the placebo group to 11.5% in the group receiving
lumiracoxib 100 mg twice daily. Moderate to severe edema
was reported in 4% of patients receiving diclofenac 75 mg
twice daily, in 1% of those receiving lumiracoxib (all
dosages), and in none of the patients who received placebo. There was no evidence of dosage-dependent edema
in the lumiracoxib groups and no moderate to severe
edema was seen at the highest doses. No SAEs were reported in any of the active treatment groups. One SAE was
reported for a patient randomized to placebo. In general,
notable abnormal laboratory test results did not follow any
clinically relevant pattern in any treatment group.
Discontinuations due to AEs were similar among each of
the lumiracoxib treatment groups and placebo. However,
there were more discontinuations due to AEs in the diclofenac 75 mg twice daily group (14%) than in the placebo (4%) and lumiracoxib (3–5%) groups.
DISCUSSION
The results presented here demonstrate the efficacy of the
novel COX-2–selective inhibitor lumiracoxib in relieving
the signs and symptoms of OA. Four dosages of lumiracoxib (50 mg twice daily, 100 mg twice daily, 200 mg twice
daily, and 400 mg once daily) were tested to establish the
minimum effective dosage regimen for the treatment of
OA. In terms of overall joint pain intensity, all dosages of
lumiracoxib afforded significantly greater pain relief than
placebo over 4 weeks of treatment. Throughout the study,
all dosages of lumiracoxib were equally effective in lowering pain intensity, although at week 1 there was a modestly greater improvement in pain relief with the 400 mg
once daily lumiracoxib dose when compared with the 50
and 100 mg twice daily doses.
All secondary efficacy endpoints supported these observations. Each of the WOMAC subscales demonstrated significant differences at week 4 between each of the active
agents and placebo. Similarly, changes in patient and physician global assessment of disease activity, as well as the
HAQ score, showed consistent significant differences between all active arms and placebo. No consistent significant differences in these endpoints were observed between
the different lumiracoxib dosages.
Lumiracoxib Versus Diclofenac in Osteoarthritis
A comparison of a once-daily versus a twice-daily dosing regimen of lumiracoxib was specifically undertaken in
this study. No significant differences in efficacy measures
were seen between the lumiracoxib 400 mg once-daily and
200 mg twice-daily dosing regimens, and both were comparable in terms of efficacy to the maximum therapeutic
dosage of diclofenac used in this study. These data support
the once-daily dosing option with lumiracoxib, which has
important implications for convenience and compliance
with therapy. This is particularly important among elderly
patients who often find multiple daily dosing regimens
difficult to adhere to or complex (39,40).
The sustained efficacy of lumiracoxib in relieving pain
over 24 hours stands in distinction to the pharmacokinetic
profile of this drug, as lumiracoxib has a relatively short
plasma half-life (plasma t ⁄ of 3– 6 hours) (41). The basis
for the prolonged pharmacodynamic action of lumiracoxib
is unknown but may relate to the fact that it is an acidic
compound, unlike the other currently available COX-2
inhibitors. Acidic NSAIDs are known to be retained over
time at higher concentrations in synovial fluid compared
with plasma (42). Diclofenac, an acidic dual-inhibitor
NSAID, has been shown by several investigators to have a
longer half-life in synovial fluid than in plasma in patients
with synovial effusions (43– 47) and the efficacy of diclofenac administered twice daily has been shown to be more
consistent with its pharmacokinetic profile in synovial
fluid rather than in plasma (48). Similarly, data demonstrate that the synovial fluid half-life of lumiracoxib is
prolonged compared with its plasma half-life (49,50).
Thus, regardless of its relatively short plasma half-life,
lumiracoxib administered once daily has been shown in
this study to provide excellent sustained pain relief, comparable to one of the current standard therapies for OA.
The short plasma half-life coupled with once-daily dosing
may also prove beneficial in reducing some exposurerelated side effects, but this requires evaluation in further
studies specifically focused on this issue.
In this study, the overall number of AEs was small in all
treatment groups, but discontinuations were primarily related to AEs associated with the GI system. There was no
evidence of a relationship between lumiracoxib dosage
and the frequency of AEs. Gastrointestinal AEs occurred
more frequently in the diclofenac 75 mg twice daily group
than in any lumiracoxib group or the placebo group. Specifically, the incidence of GI AEs was markedly lower in
patients treated with lumiracoxib than in those who received diclofenac 75 mg twice daily, indicating that lumiracoxib is significantly better tolerated in the GI system.
These results are consistent with previous reports of the
low rate of GI adverse effects with other COX-2–selective
inhibitors (15,19,20,25,26,28,51). Differences in the rates
of other AEs between patients treated with lumiracoxib
and either placebo or diclofenac were not marked. The
study was too small and not designed to detect clinically
meaningful differences in most safety endpoints.
In summary, over the 4-week period of this study, lumiracoxib provided effective relief from the symptoms of OA
(pain and stiffness), improved overall physical function,
and was well tolerated. All dosage regimens of lumiracoxib were significantly more effective than placebo and
12
555
comparable to diclofenac in relieving the signs and symptoms of OA. Lumiracoxib had a tolerability profile comparable to that of placebo and superior GI tolerability, even at
the highest dosage studied, compared with the nonselective NSAID diclofenac (75 mg twice daily), while providing similar efficacy.
Because all lumiracoxib dosages used in this trial
showed superior efficacy to placebo, additional studies of
longer duration with larger patient populations evaluating
different total daily dosages of lumiracoxib as well as
once-daily dosing regimens are warranted. Furthermore,
trials of longer duration with larger patient populations
will be needed to confirm both the efficacy data from this
trial as well as obtain additional information regarding the
safety of lumiracoxib. Results from this phase II study thus
provide initial evidence that lumiracoxib is an effective,
well-tolerated alternative to traditional NSAIDs for the
treatment of pain and inflammation associated with OA.
ACKNOWLEDGMENT
The authors gratefully acknowledge the contribution made
by K. Burger.
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APPENDIX A: INVESTIGATORS
In Belgium: Dr. P. Geusens (Diepenbeek); Dr. M. Malaise
(Liege); Dr. F. Raeman (Merksem); and Dr. W. Verdickt
(Turnhout). In Denmark: Dr. T. Aaboe (Copenhagen NV);
Dr. J. Beier (Odense C); Dr. H. Bliddak (Frederiksberg); Dr.
E. Gustavsen (Aarhus C); and Dr. H. H. Ibfelt (Hilleroed). In
Hungary: Dr. G. Genti (Kistarcsa); Dr. G. Poór (Budapest);
Dr. F. Szanyo (Gyor); and Dr. L. Tamasi (Miskolc). In
Germany: Dr. H. Grobecker (Regensburg); Dr. A. Rump
(Freiburg); Dr. E. Schell (Nuernberg); Dr. H. Schneider
557
(Messkirch); and Dr. H. U. Wilhelm (Stuttgart). In Switzerland: Dr. A. Aeschlimann (Zurzach); Dr. F. Hasler (Chur);
Dr. P. Hasler (Basel); Dr. T. Lehmann (Bern); and Dr. R.
Theiler (Aarau). In the UK: Dr. G. Charlwood (Kent); Dr. J.
Fraser (Wigan); Dr. J. Miller (Cheshire); Dr. S. Patel
(County Durham); Dr. J. Robinson (Liverpool); Dr. M. Salman (Oxfordshire); and Dr. B. Silvert (Bolton). In the US:
Dr. G. Botstein (Suwanee, GA); Dr. J. Cush (Dallas, TX); Dr.
J. Ervin (Kansas City, MO); Dr. K. Fye (San Francisco, CA);
Dr. M. Greenwald (Rancho Mirage, CA); Dr. E. Hurd (Dallas, TX); Dr. S. Krumholz (West Palm Beach, FL); Dr. K.
Lucas (Atlanta, GA); Dr. W. Palmer (Omaha, NE); Dr. J.
Perkins (Boulder, CO); Dr. J. Rosen (Coral Gables, FL); Dr.
C. Saadeh (Amarillo, TX); Dr. M. Sack (Austin, TX); Dr. T.
Schnitzer (Chicago, IL); Dr. L. Taber (Phoenix, AZ); Dr. A.
Weaver (Lincoln, NE); Dr. R. Williams (Augusta, GA); and
Dr. D. Yocum (Tucson, AZ).
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