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Lumiracoxib in the Treatment of Osteoarthritis, Rheumatoid Arthritis and Acute Postoperative Dental Pain: Results of Three Dose-Response Studies

Posted on: Thursday, 17 March 2005, 03:00 CST

Key words: Cyclo-oxygenase - Dental pain - Lumiracoxib - Osteoarthritis - Rheumatoid arthritis

ABSTRACT

Objectives: Overview of three dose-response studies demonstrating the efficacy of lumiracoxib, a novel COX-2 selective inhibitor, for chronic pain associated with osteoarthritis (OA), or rheumatoid arthritis (RA) and acute pain following dental extraction.

Methods: OA and RA: 4-week, randomized, placebo- and active- controlled studies of similar design. Patients (OA, n = 583; RA, n = 571) received lumiracoxib 50 mg, 100 mg or 200 mg twice daily (bid), lumiracoxib 400 mg once daily (od), diclofenac 75 mg bid or placebo. Dental: 12-h, single-center, randomized, placebo- and active- controlled study. Patients (n = 202) received single oral doses of lumiracoxib 100mg or 400 mg, ibuprofen 400 mg or placebo.

Main outcome measures: OA: pain intensity (PI) in the target joint (visual analogue scale [VAS]) and WOMAC score at Week 4; RA: overall PI (VAS) and ACR20 response at Week 4; Dental: difference (PID, categorical and VAS) score over 12 h post dose, time to onset of analgesia.

Results: Throughout the OA study, all lumiracoxib doses provided superior reductions in Pl versus placebo and at Week 4, all lumiracoxib doses provided efficacy similar to each other and to diclofenac. In the RA study, lumiracoxib 100 mg bid, 200 mg bid and 400 mg od were significantly better than placebo in Pl at Weeks 1 and 2 (all p < 0.05) but demonstrated borderline significance at Week 4 (lumiracoxib 400 mg od, p = 0.06). In pain following dental surgery, PID scores for both lumiracoxib doses were superior to placebo from 1.5 h onwards and always comparable, or superior, to ibuprofen. Lumiracoxib 400 mg had the fastest onset of analgesia, measured as median time to confirmed first perceptible pain relief using the two-stopwatch method (37.4 min, superiority versus placebo, p < 0.001). Lumiracoxib was well tolerated in all studies.

Conclusions: These studies provide initial evidence that lumiracoxib is an effective, well-tolerated agent for the treatment of chronic and acute pain.

Introduction

Traditional nonselective nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit both the constitutively expressed cyclooxygenase-1 (COX-1) isoform of COX, which generates prostaglandins cytoprotective to the gastrointestinal (GI) tract1-2, and the inducible COX-2 isoform responsible for the synthesis of prostaglandins that mediate pain and inflammation3,4. Inhibition of the COX-1 isoform by traditional NSAIDs is believed to explain the high incidence of GI-related adverse events (AEs) associated with this class of drugs. In contrast, COX-2 selective inhibitors are associated with significantly fewer GI AEs than traditional NSAIDs5,6.

Lumiracoxib (Prexige*) is a novel COX-2 selective inhibitor, which is being developed for the treatment of osteoarthritis (OA), rheumatoid arthritis (RA) and acute pain. Selectivity of lumiracoxib for COX-2 over COX-1 has been demonstrated in vitro and in vivo1 and is maintained ex vivo at doses of 800 mg8. Lumiracoxib demonstrates good oral bioavailability (74%), is rapidly absorbed (median time to maximal plasma concentration of 2 h-3 h) and is rapidly cleared from plasma resulting in a short plasma half-life (3h-6h)8-10.

Lumiracoxib is structurally distinct from other COX2 selective inhibitors in that it lacks a sulfur-containing moiety but possesses a carboxylic acid group, which confers mildly acidic properties (pKa 4.7]11. This acidity may be the reason for its distinct pharmacokinetic and pharmacodynamic profile, as weak acids have been shown to be readily sequestered into acidic environments such as inflamed joints12. For example, in animal models, lumiracoxib is characterized by preferential distribution into inflamed tissue, an effect seen with acidic NSAIDs13 but not with other COX-2 selective inhibitors14,15. Furthermore, in patients with RA, lumiracoxib demonstrates rapid absorption and sustained high concentrations in synovial fluid compared with plasma16.

This pharmacologic profile suggests that further evaluation of lumiracoxib in acute and chronic pain states is warranted. This overview describes three key dose-response Phase II studies of the efficacy and tolerability of lumiracoxib in the management of OA, RA and pain following dental surgery.

Patients and methods

Lumiracoxib in OA and RA

Two 4-week pilot studies of similar design (one each in OA and RA) were conducted to evaluate the doseresponse of 4 different doses of the COX-2 selective inhibitor, lumiracoxib. Both studies were Phase II, randomized, double-blind, double-dummy, placebo- and active-controlled, parallel-group, multinational studies. The OA study was conducted at 50 centers in seven countries and the RA study at 56 centers in five countries. Diclofenac was used as the reference therapy in both studies at the generally accepted maximum therapeutic dosage (75 mg bid). Both studies were approved by the appropriate institutional review boards and conducted according to Good Clinical Practice and in accordance with the Declaration of Helsinki (1964 and subsequent revisions). All patients provided written informed consent prior to any study procedure.

Patients

Adult patients (aged 18 years-75 years) were eligible for inclusion into the OA trial if they had a clinical and/or radiologie diagnosis of primary OA of the knee or hip (based on American College of Rheumatology [ACR] criteria)17,18; inclusion in the RA trial required a diagnosis of RA as confirmed by ACR criteria (functional status Class I-III)19,20. All patients must have been symptomatic for at least 3 months prior to enrolment. Patients were eligible regardless of previous NSAID or simple analgesic treatment. Patients were required to have pain intensity during the 24 h prior to randomization of at least 40 mm on a 100 mm visual analogue scale (VAS; 0 mm representing no pain and 100 mm representing very severe pain). Females of childbearing age were eligible only if they were not pregnant and using an acceptable form of contraception or they were not of childbearing potential.

Patients were excluded from the OA trial if they had secondary OA, had a history of, or evidence of, prespecified confounding disorders (e.g. septic arthritis, inflammatory joint disease, gout, Paget's disease or articular fracture) or had used systemic corticosteroids (except topical, eye drops, nasal, or inhaled for asthma) in the previous month. Patients were excluded from the RA trial if they were undergoing treatment with diseasemodifying antirheumatic drugs (DMARDs) and systemic corticosteroids, unless a stable regimen of ≤ 2 DMARDs or corticosteroids (≤ 7.5 mg/day of prednisone or equivalent) was established and maintained. Exclusion criteria common to both studies included significant medical problems, history of GI bleeding, open knee or hip surgery within 1 year prior to study entry, anemia or hepatic, renal, or blood coagulation disorders. Potentially confounding concomitant treatment including physiotherapy, any NSAID, intra-articular injection into the target joint, chondroitin sulfate, glucosamine sulfate, diacerhein, minocycline, H^sub 2^-blockers, proton-pump inhibitors, misoprostol or antacids were not permitted during the study period. Low dose aspirin (≤ 325 mg/ day) was permitted for cardioprotection if treatment had been initiated before the screening visit and remained stable for the whole study duration.

Demographic and medical background information and concomitant medications were recorded at screening (Visit 1). After a NSAID/ analgesic washout period of 3days-7days; during which there was no requirement for an increase in pain level (flare), eligible patients were randomized (Visit 2) to lumiracoxib 50 mg twice daily (bid), lumiracoxib 100mg bid, lumiracoxib 200mg bid, lumiracoxib 400 mg od, diclofenac 75mg bid or placebo, for 4 weeks. The lack of a flare requirement in both the OA and RA study was intended to replicate the 'reallife' clinical situation for patients with these conditions. Patients were permitted a maximum of 6 tablets (total dose 3 g) of paracetamol per day as rescue medication. Compliance and use of rescue medication were assessed through direct questioning and capsule/tablet counting.

Outcome measures

The primary efficacy variable in the OA study was the overall joint pain intensity over the previous 24 h in the most severely affected (target) joint (hip or knee), assessed using a 100 mm VAS after 4 weeks of treatment. Pain intensity was assessed by asking patients: 'Please indicate with a vertical mark through the horizontal line the most pain you had from your OA joint over the last 24 h'. The joint assessed was the one most severely affected at screening and this joint was evaluated for the entire study. Other key efficacy variables included pain intensity in the target joint (VAS) by visit (i.e. at Weeks 1 and 2) and scores at Week 4 (change from baseline) for Pain, Stiffness and Physical function (Difficulty in Performing Daily Activities, DPDA) based on the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC 3.1 Likert questionnaire) subscales21.

As in the OA study, the primary efficacy variable in the RAstudy was overall RA pain intensity over the previous 24 h assessed using a 100mm VAS after 4 weeks of treatment. Here, pain intensity was assessed by asking patients to 'indicate with a vertical mark through the horizontal line the most pain you had from your RA over the last 24h'. Other efficacy variables included overall pain intensity (VAS) by visit (i.e. at Weeks 1 and 2), response to treatment according to ACR20 criteria22, patient's and physician's global assessments of disease activity (VAS), rescue medication use, swollen and tender 28-joint count, assessment of functional status (Health Assessment Questionnaire, HAQ) and rheumatoid arthritis- specific quality of life (RAQoL questionnaire).

Safety and tolerability were evaluated throughout both studies using AEs, vital signs, clinical laboratory tests and ECG recordings. AEs were graded prior to unblinding. This was based on qualitative assessment of the extent or intensity of the AE and the possible relationship of the AE to the study drug, by the investigator, or as reported by the patient. Serious AEs (SAEs) were defined as any event that was fatal or considered life-threatening, which required or prolonged hospitalization, caused permanent disability or constituted cancer or congenital anomaly.

Statistical analyses

In both studies, descriptive statistics were used to summarize demographics and baseline characteristics. Efficacy analyses were performed using a modified intentto-treat (ITT) population, defined as all randomized patients who received at least one dose of study medication and had at least one post-baseline assessment. In each study, the confirmatory analysis for the primary efficacy variable was performed on the ITT population to determine the minimum effective detectable regimen. The closed version of the multiple union intersection procedure of the Dunnett test according to Marcus et al.23,24 was used to compare each lumiracoxib regimen with placebo with respect to the primary efficacy variable, pain intensity at Week 4. The least square means used in the pairwise comparisons were obtained using an analysis of covariance (ANCOVA) model with treatment and center as factors and baseline PI as the covariate.

In RA, ACR20 response was analyzed using a logistic regression model with treatment, country and overall pain at baseline as factors. For other efficacy variables, treatment groups were compared using an analysis of covariance model with treatment, center and baseline as factors. The secondary analyses in both studies were not adjusted for multiplicity. A last observation carried forward approach (LOCF) was used to impute missing data for time-specific variables. All patients who were randomized and had received at least one dose of study medication were included in the safety evaluation.

Lumiracoxib in pain following dental surgery

This single-center, randomized, double-blind, placeboand active- controlled, parallel-group, 12-h study was performed to evaluate the analgesic efficacy and tolerability of single oral doses of lumiracoxib, compared with placebo and ibuprofen using the acute postoperative dental pain model. Healthy males and females aged ≥ 17 years who experienced moderate-to-severe pain within 5 h of surgical extraction of two or more impacted third molar (at least one mandibular) teeth were eligible for inclusion.

Extractions were performed using a standard surgical technique with short-acting local anesthesia and nitrous oxide. Females of childbearing potential were eligible only if they were not pregnant and were using an acceptable form of contraception. Patients were excluded from the study if they had received any analgesic medication or methylphenidate hydrochloride within 48 h prior to surgery. The use of heparin or coumarin-type anticoagulants, tricyclic antidepressants, tranquillizers, muscle relaxants, lithium or narcotics was not permitted from 2 weeks prior to surgery until completion of the study. Additional exclusion criteria included known hypersensitivity to traditional NSAIDs, aspirin or paracetamol, a history or signs of any severe or uncontrolled medical condition likely to affect the safety and/or efficacy of the trial medications, a history of GI disease or bleeding, or an active peptic ulcer.

Demographic and medical background information and concomitant medications were recorded at screening (Visit 1, within 14 days prior to randomization). At Visit 2, following third molar extraction, eligible patients with moderate-to-severe pain were randomized to receive a single oral dose of lumiracoxib 100mg, lumiracoxib 400 mg, ibuprofen 400 mg or placebo.

Outcome measures

The primary efficacy outcome in this study was the time-specific pain intensity difference (PID [calculated as pain intensity at baseline minus pain intensity at each timepoint]) score based on a categorical scale. PID (categorical) was used to determine if the primary objective of the study was met, i.e. was single-dose lumiracoxib 100 mg and 400 mg effective at each post-dose timepoint when compared with placebo, and comparable to single-dose ibuprofen 400 mg.

Assessment of PID was performed at baseline and at scheduled timepoints up to 12 h post dose (15 min, 30 min, 45 min, 60 min, 90 min, and 120 min, and then hourly thereafter) using the categorical scale (0 = none, 1 = mild, 2 = moderate, 3 = severe). Time-specific PID was also assessed according to a 100mm VAS and time to onset of analgesia was determined using the two-stopwatch method. If necessary, patients were allowed rescue medication consisting of hydrocodone bitartrate/paracetamol 5mg/500mg or paracetamol 1000mg at any time during the 12-h post-dose period. Once rescue medication was used, no further efficacy evaluations were performed. AEs were recorded during the 12h assessment period. Vital signs were assessed and laboratory evaluations were performed prior to administration of study drug, and at study end.

Statistical analyses

All efficacy analyses were performed on the ITT population which included all randomized patients who were not prematurely discontinued from the study in the first hour and from whom at least one post-baseline efficacy measurement was obtained. As all patients remained in the study for at least 1 h and had at least one post- baseline efficacy measurement, the ITT population included all randomized patients. PID (categorical) was analyzed at each timepoint using an analysis of variance (ANOVA) model with treatment, number of teeth removed and PI (categorical) at baseline as factors. Pairwise comparisons were performed using Fisher's protected least significant difference method. The LOCF method was used to impute missing PI values. To estimate time to onset of analgesia, patients were instructed to stop the first stopwatch when pain relief was first 'perceptible' and the second stopwatch when pain relief was first considered 'meaningful'. If a patient stopped both stopwatches, the time to onset of analgesia was taken as the time recorded by the first stopwatch (confirmed first perceptible relief). Median times to onset of analgesia were evaluated using a Kaplan-Meier product limit estimator. Pairwise comparisons of treatment groups were performed using the logrank test and following Fisher's protected least significant difference method.

Results

Lumiracoxib in OA and RA

Treatment groups were well matched within each study. There were no relevant differences in baseline demographics or disease characteristics although, as expected, the mean age in patients with RA tended to be lower than in patients with OA (Table 1). In the OA study, 583 patients were randomized to receive lumiracoxib 50mg bid (n = 98), lumiracoxib 100mg bid (n = 96), lumiracoxib 200 mg bid (n = 99), lumiracoxib 400mg od (n = 99), diclofenac 75mg bid (n = 94) or placebo (n = 97). In the RA study, the patient numbers were; 571, 102, 98, 94, 87, 91, and 99, respectively. In both studies, mean exposure to study treatment ranged from 26 days to 28 days and discontinuation rates were similar across treatment groups with no apparent dose relationship (Table 2). In both the OA and RA studies, mean pain intensity (VAS) scores at baseline were similar for all treatment arms (range 64.7mm-67.9mm and 64.4mm-66.6mm, respectively).

Efficacy assessments

In patients with OA, mean overall scores for pain intensity in the target joint (VAS) were reduced with active treatment (all doses of lumiracoxib and diclofenac) from 64.7mm-67.0mm at baseline to 33.7mm-38.4mm at Week 4 and from 67.9mm to 50.2mm with placebo (Figure 1). All doses of lumiracoxib were significantly more effective than placebo in reducing joint pain intensity at all timepoints (all p ≤ 0.002).

Table 1. Patient characteristics and baseline disease characteristics in the OA and RA studies

Table 2. Patient disposition in the OA and RA studies

In RA, 4 weeks of active treatment with the lumiracoxib doses studied reduced mean overall pain intensity [VAS) scores from 64.3mm- 66.1 mm at baseline to 41.0mm-45.0mm at Week 4, compared with changes from 65.2mm to 40.6mm for diclofenac and 66.6mm to 48.0mm for placebo (Figure 2, Table 3). Lumiracoxib 100 mg bid, 200 mg bid and 400 mg od were significantly better than placebo at Week 1 and Week 2 (all p < 0.05) but not at Week 4 (p = 0.06 for lumiracoxib 400 mg od) while diclofenac was significantly better than placebo at all timepoints (p < 0.05).

Of note, in both the OA and RA studies, all doses of lumiracoxib were similar to each other and to diclofenac at Week 4.

The three WOMAC, Pain, Stiffness and Physical function (DPDA) subscales were assessed as secondary efficacy measures in patients with OA. The WOMAC score (at Week 4) was significantly superior to placebo for all doses of lumiracoxib and diclofenac, with regard to pain (all p < 0.006), physical function (all p < 0.001, lumiracoxib 100mg bid p = 0.056) and stiffness (all p ≤ \1.05). At Week 4, all lumiracoxib doses were generally similar to diclofenac with respect to the WOMAC subscales.

Figure 1. Mean (SD) overall pain intensity in patients with primary osteoarthritis of the knee or hip (100 mm VAS)

Figure 2. Mean (SD) overall pain intensity in adult patients with rheumatoid arthritis (100 mm VAS)

In the RA study, in terms of ACR20 responders, no significant difference was seen at Week 4 in the proportion of responders in the lumiracoxib 50 mg bid (26.5%, η = 27), lumiracoxib 100mg bid (26.8%, n = 26), lumiracoxib 200mg bid (30.1%, n = 28), lumiracoxib 400mg od (32.2%, n = 28) or diclofenac (25.3%, n = 23) groups and the placebo (20.2%, n = 20) group, nor between any of the lumiracoxib doses or between any lumiracoxib dose and diclofenac. Results for other secondary efficacy variables were generally similar to those for overall pain intensity with significance evident at Week 2 for lumiracoxib and diclofenac vs placebo but not at Week 4 (data not shown).

Rescue medication use

In the OA study, mean rescue medication use by the placebo group (1.1 tablets/day) was greater than that used by each of the active treatment groups (range 0.4 tablets/day-0.6 tablets/day). A similar trend was seen in the RA study, where mean rescue medication use by the placebo group (1.5 tablets/day] was greater than in any of the active treatment groups (range 0.7 tablets/ day-1.0 tablets/day). The proportion of patients in the OA study requiring rescue medication was significantly higher in the placebo group (67.7%) compared with the lumiracoxib 50mg bid (56.3%, p = 0.042), lumiracoxib 400mg od (50.0%, ρ = 0.002) and diclofenac (47.9%, p = 0.002) groups. Again, a similar trend was seen in the RA study, where the proportion of patients requiring rescue medication was significantly higher in the placebo group (92.9%) compared with each of the active treatment arms (71.0%-82.8%, p < 0.05).

Table 3. Mean (SD) overall pain intensity in adult patients with rheumatoid arthritis (VAS mm)

Safety and tolerability

The majority of AEs in both studies were mild-tomoderate in intensity and mainly affected the GI tract (Table 4). The incidence of AEs was similar across the lumiracoxib and placebo groups. AEs (including those considered drug-related) were reported more frequently for diclofenac than for lumiracoxib. Discontinuations due to any AE were higher for diclofenac compared with lumiracoxib. In the OA study, no SAEs were reported in any of the active treatment groups and one SAE was reported for a patient receiving placebo (severe bronchospasm with hypoxia). SAEs were reported in five patients with RA: lumiracoxib 100 mg bid (n = 1, 1.0%, mammary carcinoma), lumiracoxib 200 mg bid (n = 1, 1.1%, pyelonephritis), lumiracoxib 400 mg od (n = 2, 2.3%, peripheral vestibular lesion, hypertension with ECG changes) and diclofenac (n = 1, 1.1%, anemia). However, only one SAE in the RA study was suspected by the investigator to be drug-related (hypertension with ECG changes in the lumiracoxib 400 mg od group). Changes in vital signs and ECG parameters were similar across treatment groups but were not considered clinically relevant. This pattern in OA and RA was maintained with regard to abnormal laboratory values, in that, notable elevations in laboratory safety analytes (mean changes versus placebo) with diclofenac or any lumiracoxib dose were infrequent and did not follow any clinically relevant trend. In the OA study, a few isolated abnormal (≥ 3 X ULN) alanine aminotransferase (ALT) and aspartate aminotransferase levels were recorded in the lumiracoxib 200 mg bid (n = 3 patients) and 400 mg od groups (n = 2 patient). A similarly low number was seen in the RA study, where notable increases in ALT levels were seen in the lumiracoxib 200 mg bid (n = 1 patient), lumiracoxib 400 mg od (n = 1 patient) and diclofenac (n = 2 patients) groups. Events occurring during treatment were generally attributed, by the investigator, to the patients' medical history or concomitant problems. All other events occurred after discontinuation.

Table 4. Summary of AEs in the OA and RA studies (≥ 5% incidence in any treatment group)

Lumiracoxib in pain following dental surgery

In total, 202 patients were randomized to receive a single oral dose of lumiracoxib 100 mg (n = 51), lumiracoxib 400 mg (n = 50), ibuprofen 400 mg (n = 51) or placebo (n = 50). There were no notable differences in demographic or baseline characteristics between the four treatment groups. Randomized patients were of mean age 22.0 4.9 years (range 17years57 years), predominantly female (61.9%) and Caucasian (67.3%). A total of 57 (28.2%) patients completed the study (Table 5). The majority of discontinuations resulted from patients taking rescue medication. Only one patient, in the ibuprofen 400 mg group, withdrew due to an AE (postoperative bleeding at the suture site).

Efficacy assessments

PID (categorical) scores for lumiracoxib 400 mg, lumiracoxib 100 mg and ibuprofen 400 mg were significantly superior to placebo (p < 0.05) (Figure 3). This was seen at all timepoints from 1 h through 12 h post dose for lumiracoxib 400mg and ibuprofen 400mg, and from 1.5h to 9h (inclusive) for lumiracoxib 100 mg. Mean PID scores for lumiracoxib 400 mg were comparable with ibuprofen 400 mg up to 4 h post dose but superior to ibuprofen from 5 h onwards. Mean PID scores for lumiracoxib 100 mg were similar to ibuprofen 400 mg throughout the post-dose study period. The results for PID (VAS) were generally similar and consistent with those for PID (categorical).

Lumiracoxib 400 mg demonstrated the fastest time to onset of analgesia (median 37.4 min) followed by ibuprofen 400mg (median 41.5min), lumiracoxib 100 mg (median 52.4min) and placebo (median ≥ 12 h) (Table 6). The times to onset of analgesia were significantly faster for all active treatments compared with placebo (all p ≤ 0.001) and there was no significant difference between either of the two lumiracoxib doses and ibuprofen.

Table 5. Patient disposition in the study of pain relief following dental surgery

Figure 3. Mean PID scores in patients with postoperative dental pain (categorical scale)

Table 6. Time to onset of analgesia in postoperative dental pain study

Safety and tolerability

The majority of events were of mild or moderate severity and involved GI disturbances such as nausea, emesis, and diarrhea. The greatest incidence of AEs was seen in the placebo group (20% of patients experiencing any AE) compared with 14%, 2%, and 10% of patients in the lumiracoxib 100mg, lumiracoxib 400 rng and ibuprofen 400 mg groups, respectively. The GI AEs were reported by 14%, 6%, 2%, and 8% of patients in the placebo, lumiracoxib 100mg, lumiracoxib 400mg, and ibuprofen 400 mg groups, respectively, and the majority were related to the postoperative status of the patient. No SAEs were reported in any active treatment group. However, one SAE occurred in the placebo group (deep vein thrombosis]. There were no notable changes from baseline in vital signs or clinical laboratory parameters.

Discussion

This paper describes the findings from three doseresponse Phase II trials conducted to evaluate the efficacy of lumiracoxib in relieving chronic pain associated with OA and RA and for the relief of acute pain following dental surgery. In these studies, lumiracoxib demonstrated similar efficacy to traditional NSAIDs across three disparate indications coupled with better tolerability than diclofenac in OA and RA. Specifically, lumiracoxib was shown to provide effective relief from pain and stiffness and improve functional status in OA. A similar trend was seen in RA, although comparison of lumiracoxib with placebo reached only borderline significance at study endpoint, Week 4, despite significant differences having been seen earlier in the study at Week 1 and Week 2. Single-dose lumiracoxib was also shown to provide effective rapid analgesia in patients with acute pain following dental surgery.

In patients with OA, all lumiracoxib doses were superior to placebo at all timepoints for the primary efficacy variable, pain intensity in the target joint (VAS), and 50mg bid was found to be the minimum effective dose in the confirmatory analysis. In patients with RA, treatment with lumiracoxib 50 mg bid showed no difference from placebo at any timepoint, and hence defined this as a non- effective dose. In contrast, all other lumiracoxib groups (100mg bid, 200mg bid, and 400 mg od), showed superiority from placebo at Week 1 and Week 2, suggesting that the minimally effective lumiracoxib dose tested was 100 mg bid. At the Week 4 timepoint, however, no statistically significant difference was seen between patients treated with any of the lumiracoxib doses and those treated with placebo with regard to either the primary endpoint or the ACR20 response endpoint. Surprisingly, patients treated with diclofenac, the active control in this study, also failed to show a statistically significant difference from placebo in the ACR20 response at Week 4, suggesting that some aspect of the study design or implementation may have confounded the outcome. The lack of a flare design may have reduced the likelihood of finding a difference, as other studies have demonstrated such effects. Additionally, the continued clinical improvement of the placebo group may have been significantly influenced by increasing use of rescue medication, which was greater in this group than in the active treatment groups.

In patients with acute pain following dental surgery, single doses of lumiracoxib 100 mg and 400 mg provided a statistically superior PID compared to placebo at most post-dose timepoints and a significantly faster time to onset of analgesia when compared with placebo. Notably, for both PID and time to onset of analgesia, each dose of lumiracoxib was comparable or superior to ibuprofen, an agent considered particu\larly effective in the management of pain following dental surgery and, as such, widely regarded a first choice regimen25,26.

All three studies were of short duration with relatively few patients and were not designed to detect clinically meaningful differences in most safety endpoints. Therefore, firm conclusions regarding safety and tolerability could not be drawn. However, all studied doses of lumiracoxib were well tolerated and there was no apparent dose-relationship between lumiracoxib and the incidence of any AE. In the OA and RA studies presented here, lumiracoxib was better tolerated by patients compared with diclofenac, complementing earlier observations with naproxen in healthy subjects27. In particular, the incidence of GI-related AEs was markedly lower in patients treated with lumiracoxib than in those who received diclofenac, supporting the superiority of COX-2 selective inhibitors on reducing GI symptomatology compared with traditional nonselective NSAIDs. As might be expected, the majority of AEs in the study of pain following dental surgery were related to the postoperative status of the patient.

A recent systematic review of population-based epidemiological studies estimated a slight, but nonsignificant increase in liver injury with NSAID use28. In the OA and RA studies reported here, occasional, transient increases in liver function parameters were observed with lumiracoxib and diclofenac. These were not associated with any clinical symptoms. Larger, longer-term studies will provide more robust information regarding the hepatic safety and tolerability of lumiracoxib.

Conclusions

These studies provide initial evidence that lumiracoxib is an effective and well-tolerated alternative to traditional NSAIDs for the treatment of both chronic and acute pain and inflammation. Additional studies of longer duration with larger patient populations evaluating different total daily dosages of lumiracoxib, particularly once-daily dosing regimens, are warranted. Such trials will be needed to confirm both the efficacy data from these trials, as well as to obtain additional information regarding the safety of lumiracoxib. As such, these studies provide a strong platform from which the full efficacy and tolerability profile of lumiracoxib can be evaluated.

Acknowledgments

This work was supported by a grant from Novartis Pharma AG, Basel, Switzerland.

* Prexige is a registered trade name of Novartis Pharmaceuticals Corporation, East Hanover, NJ

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CrossRef links are available in the online published version of this paper:

http://www.cmrojournal.com

Paper CMRO-2786_3, Accepted for publication: 01 December 2004

Published Online: 10 January 2005

doi.10.1185/030079904X20231

Thomas J. Schnitzer(a), James R. Fricke Jr(b), Xavier Gitton(c), Sumedha Jayawardene(d) and Victor S. Sloan(d)

a Northwestern University Feinberg School of Medicine, Chicago, IL, USA

b Austin Oral and Maxillofacial Surgery Associates, Austin, Texas, USA

c Novartis Pharma AG, Basel, Switzerland

d Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA

Address for correspondence: Dr Victor S. Sloan, Director, Clinical Research, Novartis Pharmaceuticals Corporation, One Health Plaza, East Hanover, NJ 07936-1080, USA. Tel: +1 862 778 3545; Fax: +1 973 781 6793; email: victor.sloan@pharma.novartis.com

Copyright Librapharm Jan 2005

Source: Current Medical Research and Opinion

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