British Journal of Rheumatology 1996;35(8uppl.

l):35-38

A DOUBLE-BUND STUDY TO COMPARE THE EFFICACY AND SAFETY

OF MELOXICAM15 mg WITH PIROXICAM 20 mg IN PATIENTS WITH
OSTEOARTHRITIS OF THE HIP
B. LINDEN,* M. DISTELf and E. BLUHMKIJ
*Eksjd Hospital, S-S7S 81 Eksjd, Sweden andfDr Karl Thomae GmbH, Birkendorfer Strafie 65,88397
BiberachlRiss, Germany

SUMMARY
Meloxicam 15 mg once daily (n = 128) was compared with piroxicam 20 mg (n = 127) in this 6 week, double-blind, parallel-group,
randomized, multicentre study in out-patients with symptomatic osteoarthritis (OA) of the hip. Assessments of pain, global
efficacy and global tolerance were made on a 10 cm horizontal visual analogue scale; severity of OA was evaluated by Lequesne's
index. Efficacy results showed significant improvement compared with baseline, with no significant difference between meloxicam
15 mg and piroxicam 20 mg. The type and frequency of adverse events were comparable for the two drugs. The most frequent events
reported were gastrointestinal (GT) disorders, occurring in 21 and 23% of meloxicam and piroxicam patientsrespectively.The
global tolerance assessment by patients at the end of treatment favoured meloxicam. In conclusion, meloxicam at a dose of 15
mg/day is comparable in efficacy and safety to piroxicam 20 mg.
KEY WORDS: Meloxicam, Piroxicam, Osteoarthritis, NSAID, Cyclooxygenase.

SINCE no disease modifying drugs are available to treat METHODS

osteoarthritis (OA), non-steroidal anti-inflammatory
drugs (NSAIDs) are widely used since they not only
relieve pain and inflammation but also improve
function. A wide range of NSAIDs are available;
however, clinical response and undesirable effects
resulting from their use vary enormously between
patients [1]. The results of recent clinical studies have
reaffirmed that many patients prefer NSAIDs to
analgesics. Concerns about their gastrointestinal (GI)
toxicity remain. Strategies to prevent this toxicity
include the use of selective inhibitors of cyclo-
oxygenase-2 (COX-2) [2]. Drug therapy must be
adapted to suit the individual patients to take into
account the dinical heterogeneity of OA.
OA of the hip is more common in elderly people and
thus it is particularly important that safety aspects of
NSAID use, such as GI or renal adverse effects, should
be considered. The continued search for an efficacious
and well-tolerated NSAID has resulted in the develop-
ment of meloxicam [4-hydroxy-2-methyl-A^-(5-methyl-
2-thiazolyl)-2H-1,2-benzothiazine-3-carboxamide-1,1-
dioxide], a novel drug of the enolic acid class.
Meloxicam has a greater anti-inflammatory potency, in
the rat than conventional NSAIDs and shows a
particularly good gastric tolerability [3]. This is believed
to be due to its inhibition of COX-2 in preference to
COX-1 [4].
This study has investigated the efficacy and
tolerability of meloxicam in comparison with piroxicam
in patients with an established diagnosis of OA of the
hip. Piroxicam is a widely used NSAID with proven
efficacy for this condition [5-7].
Correspondence to: B. Linden, Department of Orthopaedic
Surgery, Eksjd Hospital, S-575 81 Eksj6, Sweden.
This study was of a randomized, parallel-group,
double-blind design, comparing meloxicam with
piroxicam. Twenty-two centres in Sweden, Denmark,
Belgium, The Netherlands and Germany were involved.
The protocol was approved by the appropriate Ethics
Committee(s) in each of the participating countries and
the study was carried out in accordance with the
Declaration of Helsinki. All patients gave written,
informed consent to participation in the study. Patients
were eligible for inclusion in the trial if they were at least
18 yr of age and had clinical diagnosis of OA in the hip
for at least 3 months (with radiographical confirmation
of the target hip), at least moderate pain on active
movement in the affected hip [a score of at least 35 mm
assessed by the patient on a horizontal visual analogue
scale (VAS; 0 mm = no pain, 100 mm = unbearable
pain)] and were able to perform their daily routine.
Patients receiving therapy for concomitant diseases
were allowed to continue with their medication (except
drugs excluded by the study protocol); any changes in
concomitant therapy were documented. Treatment with
other NSAIDs, any other analgesics (except para-
cetamol) or anti-inflammatory drugs was not allowed
during die study. Patients could use paracetamol as a
rescue analgesic throughout the course of the study.
Massage and exercise were also permitted, provided
that the routines continued unchanged throughout the
course of the study.
On initiation of the study, patients were randomized
into three parallel groups to receive capsules of either
meloxicam 15 mg or 30 mg or piroxicam 20 mg once
daily. The total study period was 6 weeks and patients
were assessed at the start of the study, at days 7 and 21
and at the end of the study (day 42). All patients
pretreated with NSAIDs underwent a washout period
of 3-7 days. On completion of the washout period,

O 1996 British Society for Rheumatology

36 STUDIES ON MELOXICAM (MOBIQ
patients were assessed for eligibility and treatment was
started. The primary efficacy measure for this trial was
the assessment of worst pain in the target hip upon
active movement in the previous 24 h. Secondary
outcome measures included worst pain in the target hip
at rest in the previous 24 h, global efficacy, withdrawals
due to poor efficacy, paracetamol consumption and
Lequesne's index of severity at visits 1 and 4 [8]. The
assessments of pain and global efficacy were made by
the patient, using a horizontal VAS of 100 mm. Zero
corresponded to 'no pain' for pain measurements or
'excellent' for global efficacy and 100 mm corresponded
to 'unbearable pain' or 'useless' respectively. Safety
variables were also evaluated, with the patient assessing
tolerance of the medication at each visit and global
tolerance at the end of the study. The global tolerance
assessment reflects the general impression of patient
and physician regarding overall tolerability of the test
drug throughout the study. An overall assessment of
efficacy and tolerability is required for clinical trials by
the German Health Authorities [9]. The VAS scales for
tolerance and global tolerance were defined as
'excellent' at 0 mm and 'extremely bad' at 100 mm. The
occurrence of adverse events and premature withdrawal
due to poor tolerance was also recorded.
Laboratory investigations were performed on entry
to, and on completion of, the study. These consisted of
haematological and serum chemistry measurements,
together with a urinalysis including protein, glucose and
blood cells. The plasma levels of meloxicam and
piroxicam were determined at day 21 for a compliance
check. Compliance was also assessed by counting the
number of returned capsules.
The clinical development of meloxicam 30 mg was
discontinued during the course of this trial. The results
from this group were only evaluated descriptively and
are not reported here.
Statistical analysis
It was calculated on the primary endpoint that a
sample size of at least 160 evaluable patients for each
treatment group would be sufficient to detect a
difference between the two groups of 15% or more by
means of a two-sample f-test (a = 5%, P = 10%, two-
tailed).
The differences against baseline for 'pain on
movement' and 'pain at rest' were analysed by a
treatment x centre analysis of variance. A two-sample
/-test was applied to 'pain at rest', 'global efficacy' and
'global tolerance'. The Kruskal-WaUis test was used to
test the influence of the treatment on the changes of
Total Index of Severity of OA of the hip. Results are
reported as exploratory significant if P < 0.05. No
alpha adjustment for multiple testing was foreseen. An
explanatory analysis of efficacy endpoints was
performed on patients who completed the study and
had no significant protocol violations. In addition, an
intent-to-treat analysis including all randomized
patients was performed. The last-value-carried-forward
procedure was used to adjust for missing values.
RESULTS
The trial centres and the number of patients entered
by each are listed in the acknowledgements. Two
hundred and eighty-five patients were randomized to
receive one of the three treatments (meloxicam 15 mg,
meloxicam 30 mg or piroxicam 20 mg once daily). Of
these, 29 were entered into the meloxicam 30 mg group
and were evaluated separately. Of the remaining 256
patients, 29 were excluded from the explanatory analysis
because of protocol violations; thus, 227 patients were
included in the explanatory analysis and 256 in the
intent-to-treat analysis. The demographic data from
these latter patients and reasons for withdrawal are
summarized in Table I. The patients were well matched
for age, sex, duration of OA, height and weight.
Efficacy assessments
There was no significant difference at baseline
between the two treatment groups with respect to the
primary endpoint, i.e. pain on movement. Both treat-
ment groups showed a continuous reduction in pain
during the 6 weeks of treatment, with a particularly
large decrease in the first week (Table II). There was a
consistent trend in favour of meloxicam which was
more marked towards the end of study. However, this
difference did not reach statistical significance. Similar
results were obtained in the explanatory analysis.
Table III shows the levels of worst pain in the target
joint at rest recorded by the patient. Both treatment
groups showed a marked reduction in this parameter.
The mean global efficacy scores, as assessed by the
patient at the end of the study (intent-to-treat analysis),
and the mean total index of severity of OA of the hip
after 6 weeks of treatment are shown in Table FV. There
was a slightly better global efficacy of meloxicam and
both treatment groups showed a reduction in the mean
total index of severity. All three scores of the index of
severity (pain assessment, maximum walking distance
and routine activities) were reduced.
Safety and tolerability
From the total of 256 patients treated with meloxi-
cam 15 mg or piroxicam 20 mg, 49 taking meloxicam
and 47 taking piroxicam reported one or more adverse
TABLE I
Summary table of demographic data and primary diagnosis
(mean ± sx>.; intent-to-treat analysis)
Meloxicam IS mg Piroxicam 20 mg
No. of patients 129 127
Age(yr) 67.2+12.1 67.2 ± 11.4
Height (cm) 168.1 ± 8 . 3 167.9 ± 8.4
Weight (kg) 73.1 ± 14.0 73.9 ±13.9
Female/male (%) 62.8/37.2 63.0/37.0
Duration of OA diagnosis 6.2 ± 6.4 5.5 ±4.7
(yr)
No. of patients withdrawn due to:
Adverse events 12 10
Lack of efficacy 2 4
Other reasons 2 1
 LINDEN ETAL.: MELOXICAM COMPARED WITH PIROXICAM IN OA 37

TABLEn TABLE V
Mean levels of pain on movement as f""=*fW by the patient using a Advene events leading to withdrawal (intent-to-treat analysis)
100 mm VAS intent-to-txeat analysis
Adverse events Meloxicam 15 mg (n) Piroxicam 20 mg (n)
Meloxkam IS mg Piroxicam 20 mg
Days of treatment (mean ± sx>.) (mean ±SJX) Pain 1 0
Abdominal pain 2 2
0 59.7 ± 15.2 60.2 ± 14.7 Constipation 0 1
7 41.0 ± 20.4 42.4 ± 20.0 Diarrhoea 0 3
21 36.6 ± 2 2 7 38.2 ± 23.7 Duodenal ulcer 1 0
42 31.7 ±24.3 34.9 ± 24.4 perforated
Dyspepsia 6 3
Gastric ulcer perforated 0 1
Gastritis 1 0
TABLE HI Nausea 2 1
Angina pectoris 0 1
Mean levels of worst pain at rest in the previous 24 h as assessed by
Coughing 1 0
the patient (VAS 100 mm; intent-to-treat analysis) Dyspnoea 1 1
Meloxkam 15 mg Piroxicam 20 mg Rash 0 1
Day of treatment (mean ± SJ>.) (mean ± SJ>.) Lymphadenopathy 0 1
0 34.2 ± 2 2 34.1 ±21.5 Withdrawals due to 12 10
7 21.2 ±21.1 23.2 ±21.7 advene events (n = 22)
21 18.4 ±20.3 19.4 ±23.1 Total patients (n = 256) 129 127
42 17.4 ±22.9 17.8 ±21.6

TABLE IV
Global efficacy scores as assessed by the patient at the end of the
study and the total index of severity of OA of the hip after 6 weeks
of treatment (intent-to-treat analysis)
Meloxicam 15 ing Piroxicam 20 mg
(mean ± S.D. [mm]) (mean ± S.D. [mm])
Global efficacy scores 29.9 ± 25.4 32.2 ± 27.8
(VAS: 0 mm =
excellent; 100 mm =
useless)
Reduction in the total 3.7 ± 3.6 3.4 ± 3.8
index of severity
points

events. The most frequent adverse events were disorders
of the GI system (20.9 and 22.8% in the meloxicam and
piroxicam groups respectively) and the types of adverse
events reported were similar in both treatment groups.
There was one severe GI adverse event (perforated
duodenal ulcer) in the meloxicam 15 mg group and
three such events (one patient with a perforated gastric
ulcer, one patient with duodenal ulcers and GI bleeding,
and one patient with a gastric ulcer) in the piroxicam 20
mg group. Twelve patients in the meloxicam group and
10 in the piroxicam group were withdrawn due to
adverse events; the events leading to withdrawal are
summarized in Table V. Laboratory investigations
showed no clinically relevant changes.
Tolerability of the study drugs, evaluated by the
patient at each visit, showed that both study medi-
cations were well tolerated throughout the study. The
mean (± S.D.) global tolerance values assessed by the
patient at the end of the study were 5.1 ± 13.5 mm
and 9.3 ± 18 mm (P = 0.054) in the meloxicam and
Meloxicam Piroxicam
O mm ~ •xo«n«nt
Fio. 1.—Mean (± S.D.) values of global tolerance assessed by the
patient using a 100 mm VAS (explanatory analysis).
piroxicam groups, respectively, in the explanatory
analysis (Fig. 1). The corresponding results from the
intent-to-treat analysis were 9.1 ± 20.7 (meloxicam) and
10.7 ± 20.2 mm (piroxicam).
DISCUSSION
NSAIDs are the most common form of treatment for
OA and will remain so for the foreseeable future. There
have been numerous studies demonstrating their
efficacy in this condition [5-7, 10-13], and many
millions of patients have benefited from reduced pain
and increased mobility associated with their use.
However, patients do vary in their clinical response to
NSAIDs and some will be non-responders to any given
38 STUDIES ON MELOXICAM (MOBIQ
agent [1]. For this reason, together with the requirement
for a NSAID with reduced GI toxicity, much research
continues to be directed into the production of new
drugs of this class.
Piroxicam is an established therapy for OA and it is
imperative that any new agent is at least as effective.
This study has shown that meloxicam compares well to
piroxicam in terms of both efficacy and tolerability.
With regard to the primary endpoint of this study, pain
on movement, meloxicam and piroxicam produced
considerable pain reduction during the first week of
treatment. As NSAIDs are often prescribed chronically,
continued efficacy is of primary importance. The
parameters of pain at rest and global efficacy also
demonstrated meloxicam to be at least as effective as
piroxicam. Lequesne's index of severity revealed a
reduction in pain, an improvement in the maximum
walking distance and an increased ability to perform
routine daily tasks with both therapies.
The incidence of GI side-effects is a limiting factor in
the prescription of many NSAIDs for relief of OA
symptoms. The frequency of adverse events (GI or
otherwise) and global tolerance were similar in the
meloxicam-treated and piroxicam-treated groups. The
global tolerance of the drugs assessed by the patient at
the end of the study suggested a slightly better tolerance
of meloxicam over piroxicam although this difference
was not statistically significant.
ACKNOWLEDGEMENTS
We would like to thank the investigators for their
work which made this study possible: Dr A. Hansen,
Motala Lasarett, Motala (24 patients); Dr L. Carling,
Bollnas Sjukhus, Bollnas (eight patients); Dr G.
Frenckner, Traneberg GP-Center, Bromma (six
patients); Dr B. Linden, Eksjd Hospital, Eksjo (50
patients); Dr K. Persson, Soderhamn Sjukhus, Soder-
hamn (18 patients); Dr B. Svensson, Sandviken (two
patients); Dr P. Unge, Sandviken Hospital, Sandviken
(one patient); Dr G. Gorm-Rasmussen, Odense
Hospital, Odense (16 patients); Dr L. Helleberg,
Skalskor Hospital, Skalskor (two patients); Dr H.
Henriksen, Odense (two patients); Dr B. Lund,
Tranehaven Hospital, Schioldannsvej (44 patients); Dr
O. Mune, Koldin (four patients); Dr H. Goei The, De
Wever Hospital, Heerlen (16 patients); Dr K. Han,
Rotterdam (10 patients); Dr B. Masek, St Maarten's
Hospital, Venlo (11 patients); Dr P. V. Oijen, Groot
Ziekengasthuis, Hertogenbosch (two patients); Dr D. S.
v. Reesema, The New Hospital, Warnsveld (three
patients); Dr J. Moolenburgh, Medical Centre Alkmaar,
Alkmaar (four patients); Dr L. Williame, General
Hospital Middelheim, Antwerpen (nine patients); Dr C.
Baran, Dachau (eight patients); Dr W. Hiittemann,
Aachen (16 patients); and the head of the clinical trial:
Dr Wackermann, CRF Institute for Clinical Pharmac-
ology, Arnikastr.
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