Celecoxib 200 mg q.d. is efficacious in the management of osteoarthritis of the knee or hip regardless of the time of dosing

K. Stengaard-Pedersen, R. Ekesbo1, A.-L. Karvonen2 and M. Lyster3

Rheumatology, Aarhus University Hospital, Aarhus, Denmark, 1Institution of Civic Medicine, Department of General Medicine, University Hospital, Malmö, University of Lund, Lund, Sweden, 2Medicine, University Hospital of Tampere, Tampere, Finland and 3Pfizer ApS, Ballerup, Denmark.

Correspondence to: K. Stengaard-Pedersen, Department of Rheumatology, Aarhus University Hospital, DK-8000 Aarhus C, Denmark. E-mail: stengaard{at}akh.aaa.dk


    Abstract
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Objectives. The primary objective was to demonstrate equivalence between a.m. and p.m. dosing of celecoxib 200 mg q.d. An equivalence assessment of q.d. vs b.i.d. dosing was a secondary objective.

Methods. In this randomized, double-blind study, patients with symptomatic osteoarthritis of the knee or hip were randomized to receive celecoxib 200 mg q.d. a.m., celecoxib 200 mg q.d. p.m. or celecoxib 100 mg b.i.d. The primary outcome variable, measured at week 12 on a 0- to 10-point integrated scale, was patient satisfaction assessment (pain relief, walking/bending, and willingness to continue medication). Equivalence was declared if the 95% confidence interval (CI) of the difference (a.m. q.d. vs p.m. q.d., b.i.d. vs q.d.) fell within the interval of –2 to +2.

Results. A total of 697 patients were enrolled in this trial. For the a.m. vs p.m. comparison, the 95% CIs were within the prespecified equivalence criteria for all three measures of patient satisfaction: pain relief, mean –0.2, 95% CI –0.53 to 0.68; ability to walk and bend, mean –0.2, 95% CI –0.54 to 0.64; willingness to continue medication, mean –0.7, 95% CI –0.98 to 0.49. The 95% CIs for the q.d. vs b.i.d. comparison were also within the –2 to +2 interval.

Conclusion. Regardless of the time of day at which celecoxib 200 mg q.d. is administered, patients are equally satisfied with the pain relief, ability to walk and bend, and willingness to continue medication.

KEY WORDS: Osteoarthritis, COX-2 specific inhibitor, Celecoxib, Dose regimen.


    Introduction
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Osteoarthritis (OA) is a debilitating disease that affects around 33.92 million adults in Europe alone [1]. OA of the knee and hip has a greater associated disability than OA of any other joint, although degenerative changes of the spine, hands and feet can also lead to functional limitation [2]. Age is the most powerful risk factor for OA [3], and because OA occurs most commonly in individuals aged 40 yr or over, its prevalence is expected to increase in Western countries as the overall population ages.

Celecoxib, a cyclooxygenase-2 (COX-2)-specific inhibitor, provides effective treatment of OA and rheumatoid arthritis [48] with an improved gastrointestinal and platelet safety profile compared with non-specific non-steroidal anti-inflammatory drugs (NSAIDs) [912]. Two studies have demonstrated that celecoxib 200 mg daily (q.d.; p.m. dose) and celecoxib 100 mg twice daily (b.i.d.; a.m. and p.m. doses) are equally well tolerated and effective in patients with OA [13, 14]. The comparative efficacy and safety of a.m. and p.m. dosing of celecoxib has not been studied, however. Since patients with OA often have more symptoms during the day, when they are active, a single dose in the morning may be more advantageous than an evening dose. Indeed, a previous chronotherapeutic study investigating the non-specific NSAID indomethacin in OA of the hip and knee has suggested that analgesic efficacy can vary according to ingestion time [15].

In this current study, the primary objective was to demonstrate equivalence between a.m. and p.m. dosing of celecoxib 200 mg q.d. An equivalence assessment of q.d. vs b.i.d. dosing was a secondary objective.


    Methods
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Study design
This was a multicentre, double-blind, parallel-group, randomized study in patients with symptomatic OA of the knee or hip. Patients were randomized to receive either celecoxib 200 mg q.d. a.m., celecoxib 200 mg q.d. p.m. or celecoxib 100 mg b.i.d. for 12 weeks. All patients took an a.m. and p.m. dose. For the q.d. dosing regimens, one of the doses was placebo. Patients were required to visit their general practitioner for assessment at baseline, week 6 and week 12.

Patients
Patients who were at least 40 yr old and who had experienced clinical symptoms of OA in the hip or knee at least 3 months before randomization were eligible for inclusion in this trial. All patients were required to fulfil the American College of Rheumatology classification criteria for OA in the hip or knee at the time of randomization. The inclusion criteria did not allow daily use of other analgesics, including paracetamol, opioids and conventional NSAIDs. Patients were not allowed to receive hyaluronic acid injections or corticosteroids within 3 months prior to admission. For patients receiving an anti-inflammatory drug or analgesic, a washout period of 48 h for NSAIDs and 24 h for analgesics was required prior to inclusion in the trial.

The most common concomitant medication was paracetamol and patients taking at least one dose during the study period were approximately 40% in all three treatment groups.

This study was conducted according to the principles of the Declaration of Helsinki (1996) and good clinical practice. The protocol was approved by the appropriate ethical committee in each country in which the study took place. Each patient had to provide his or her written informed consent for inclusion in this study.

Efficacy endpoints
The primary outcome variable was the patient satisfaction assessment (based on pain relief, ability to walk and bend, and willingness to continue with study medication) at week 12. Patients were asked to rate their satisfaction with pain relief and their ability to walk and bend on a 10-point scale in which 1 = very dissatisfied and 10 = very satisfied. Willingness to continue with the medication was rated on a 10-point scale in which 1 = very unwilling and 10 = very willing.

As secondary endpoints, physical function and the patient’s global assessment were evaluated at baseline and at week 12. The Western Ontario and McMaster Universities (WOMAC) Osteoarthritis Index was used to assess physical function [16]. In the patient’s global assessment of OA, patients were asked to respond to the following question: ‘Considering all the ways your osteoarthritis affects you, how are you doing today?’ using a five-point scale in which 1 = very good and 5 = very poor.

Safety and tolerability
Clinical safety was monitored for patients with at least one dose of study medication by the incidence of adverse events, physical examination and changes in clinical laboratory parameters and vital signs from baseline to week 12.

Statistics
The primary treatment comparison was between the celecoxib 200 mg q.d. a.m. and celecoxib 200 mg q.d. p.m. doses and the secondary treatment comparison was between the celecoxib 200 mg q.d. and celecoxib 100 mg b.i.d. doses. Assuming a standard error of 2.5 points on the 10-point scale for the primary efficacy measure of the patient’s satisfaction assessment, and that a difference of 2 points would show a clinically meaningful treatment effect, a sample size of 200 patients was calculated to have at least 80% power.

Efficacy analysis was carried out in the evaluable patient cohort and the three components of the patient’s satisfaction assessment were evaluated by analysis of variance (ANOVA). Two-sided 95% confidence intervals (CIs) for the differences between treatments were estimated and equivalence was declared if the 95% CI of the difference (a.m. q.d. vs p.m. q.d., b.i.d. vs q.d.) fell within the interval of –2 to +2. Changes from baseline in the secondary efficacy variables of WOMAC and patient’s assessment of OA were evaluated by ANOVA and logistic regression analysis respectively. Study centre, gender and age were included as potential covariates in these analyses. Safety analysis was performed on patients who took at least one dose of study medication.


    Results
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Patients
A total of 697 patients were enrolled, of whom 565 (81%) completed the study and 577 (83%) were eligible for inclusion in the primary analysis. Adverse event(s) was the most commonly cited reason for withdrawal, accounting for 66 patients in total. Demographic and clinical data were similar across all groups (Table 1). The ratio of males:females was approximately 1:2 and the majority of the patients were between the ages of 50 and 79 yr. The ratio of OA of the hip relative to OA of the knee was approximately 3:8 and the mean duration of OA ranged from 4.7 to 5.2 yr. No significant differences between the three groups were observed in terms of patient’s global assessment of OA or WOMAC composite score.


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TABLE 1. Patient demographics and clinical data at baseline

 
Efficacy endpoints
The mean scores at week 12 for patient satisfaction with pain relief, ability to walk and bend, and willingness to continue medication were similar across all three groups. The 95% CIs were within the prespecified equivalence criteria for both the a.m. vs p.m. and q.d. vs b.i.d. comparisons and for all three measures of patient satisfaction (Fig. 1).



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FIG. 1. Patient satisfaction at week 12: mean and 95% CIs for the a.m. vs p.m. q.d. and b.i.d. vs q.d. comparison. Patient satisfaction was rated on a 10-point scale: 1 = very dissatisfied, 10 = very satisfied.

 
The mean improvement in WOMAC composite score was likewise similar across treatment groups. The least squares mean change was –11.19, –12.23 and –11.69 in the celecoxib 200 mg a.m. q.d., celecoxib 200 mg p.m. q.d. and celecoxib 100 mg b.i.d. groups respectively). In addition, no statistically significant difference was observed in mean change in any of the three WOMAC subscales of pain, stiffness and physical function (data not shown). A similar proportion of patients in all three groups showed improvement (a reduction of at least two grades from baseline) in patient’s global assessment of OA (11, 15 and 8% in the celecoxib 200 mg a.m. q.d. group, celecoxib 200 mg p.m. and celecoxib 100 mg b.i.d. group, respectively; not significant). The least squares mean change in patient’s global assessment of OA was likewise similar across the three treatment groups (–0.49, –0.52 and –0.39 in the celecoxib 200 mg a.m. q.d., celecoxib 200 mg p.m. q.d. and celecoxib 100 mg b.i.d. groups respectively).

Safety and tolerability
Incidences of treatment-emergent adverse events were similar across all groups. The most common adverse events were diarrhoea, abdominal pain, dyspepsia and nausea, which affected 33 (4.7%), 25 (3.6%), 22 (3.2%) and 15 (2.2%) patients, respectively. The majority of adverse events were mild to moderate in severity and were not considered by the investigators to be related to the study treatment. Very few serious adverse events were observed, and only one of these was judged by the investigators to be related to treatment (urticaria in one patient in the celecoxib 100 mg b.i.d. group). No clinically meaningful changes were noted in baseline laboratory values, which included erythrocyte sedimentation rate, haemoglobin, creatinine and aspartate transaminase/alanine transaminase, in any other treatment groups.


    Discussion
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Patients were equally satisfied with the pain relief, ability to walk and bend, and willingness to continue medication that was achieved with celecoxib 200 mg daily, regardless of which of the three dosing regimens were used. In addition, patients in all three groups demonstrated improvement according to WOMAC and patient’s global assessment of OA, despite the fact that the patients were not in flare. Celecoxib was also well tolerated in this study. The results with regard to dosing frequency are consistent with those from previous studies with celecoxib that have shown equivalence of once- and twice-daily regimens in managing the pain and inflammation of arthritis [13, 14]. Unlike these previous studies, no placebo group was included in the present trial. However, the efficacy of celecoxib 200 mg/day, whether administered once daily or divided into two daily doses, has already been established clearly [47, 13, 14]. This suggests that the improvements observed in patients treated with celecoxib should be attributed to the drug’s clinical efficacy rather than to a natural improvement in the patients’ condition.

In a previous study investigating the time of treatment with indomethacin on efficacy in OA, evening ingestion was most effective in patients with predominant nocturnal or morning pain [15]. Conversely, morning or noon ingestion was most effective in patients with maximum afternoon or evening pain. This contrasts with the finding of the present study, which indicates that the efficacy of celecoxib does not depend on the time of ingestion. However, our study did not stratify patients according to whether they had morning or evening pain, so it may not be appropriate to compare them closely. Variation between the two patient populations, for example, in terms of age or comorbidities, such as renal impairment, may also account, in part, for the disparity in the studies’ findings. Other possible factors include differences between the specific pharmacokinetic profiles of indomethacin and celecoxib, such as the shorter half-life of indomethacin (4.5 vs 11 h). Further, the dosing-time dependency of different pharmacokinetic parameters has been shown to vary among different NSAIDs. For example, a dramatic change in time to peak (Tmax) and peak height of plasma concentration as well as area under the concentration time curve has been observed in response to change in time of dosing of indomethacin [17]. A chronokinetic study of ketoprofen, however, showed only Tmax to be dosing time-dependent [18].

A study investigating dosing-time-related differences in the pharmacokinetics of COX-2-specific inhibitors has not been carried out, although the present study indicates that the efficacy of celecoxib does not depend on the time of ingestion. Biochemically, the patients’ kidney and liver functions were found to be normal. The availability of the a.m. or p.m. and q.d. or b.i.d. dosing regimens used in this study provides patients and physicians with increased flexibility regarding the timing of dosing. Flexibility also exists with respect to the quantity of dosing possible for celecoxib. Previous studies have indicated that, should higher doses be required, the dose of celecoxib can be increased to achieve efficacy without the compromise of adverse events. In particular, celecoxib has demonstrated no dose-related increase in upper gastrointestinal adverse events [911] or hypertension and oedema [19, 20].

The present study, showing the equivalent efficacy of celecoxib 200 mg q.d. a.m. and celecoxib 200 mg q.d. p.m. in patients with OA provides physicians with additional flexibility for choosing an appropriate dosing regimen for their patients.

M. Lyster is employed by Pfizer Inc.


    Acknowledgments
 
The authors would like to thank Meg M. Cary for her significant contribution towards data management and analysis. This study was sponsored by Pfizer and Pharmacia Corporation.


    References
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 

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Submitted 17 May 2003; revised version accepted 25 November 2003.



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