# Abstract

 

## Background Etoricoxib is a highly selective COX-2 inhibitor which was evaluated for the treatment of rheumatoid arthritis (RA). 

## Methods Double-blind, randomized, placebo and active comparator-controlled, 12-week study conducted at 67 sites in 28 countries. Eligible patients were chronic NSAID users who demonstrated a clinical worsening of arthritis upon withdrawal of prestudy NSAIDs. Patients received either placebo, etoricoxib 90 mg once daily, or naproxen 500 mg twice daily (2:2:1 allocation ratio). Primary efficacy measures included direct assessment of arthritis by counts of tender and swollen joints, and patient and investigator global assessments of disease activity. Key secondary measures included the Stanford Health Assessment Questionnaire, patient global assessment of pain, and the percentage of patients who achieved ACR20 responder criteria response (a composite of pain, inflammation, function, and global assessments). Tolerability was assessed by adverse events and routine laboratory evaluations. 

## Results 1171 patients were screened, 891 patients were randomized (N = 357 for placebo, N = 353 for etoricoxib, and N = 181 for naproxen), and 687 completed 12 weeks of treatment (N = 242 for placebo, N = 294 for etoricoxib, and N = 151 for naproxen). Compared with patients receiving placebo, patients receiving etoricoxib and naproxen showed significant improvements in all efficacy endpoints (p\<0.05). Treatment responses were similar between the etoricoxib and naproxen groups for all endpoints. The percentage of patients who achieved ACR20 responder criteria response was 41% in the placebo group, 59% in the etoricoxib group, and 58% in the naproxen group. Etoricoxib and naproxen were both generally well tolerated. 

## Conclusions In this study, etoricoxib 90 mg once daily was more effective than placebo and similar in efficacy to naproxen 500 mg twice daily for treating patients with RA over 12 weeks. Etoricoxib 90 mg was generally well tolerated in RA patients. # Results 

## Patients Of the 1171 patients screened, 891 met eligibility criteria and were randomized. Baseline characteristics of the 891 patients in the 3 treatment groups were similar and are shown in Table [1](#). A total of 687 of the 891 patients (67.8% of the placebo group, 83.3% of the etoricoxib group, and 83.4% of the naproxen group) completed the 12-week study (Figure [1](#)). The mean number of days patients were on treatment was 65.5 for placebo, 76.0 for etoricoxib, and 76.5 for naproxen. The most common reason for discontinuation was lack of efficacy, and significantly more patients discontinued due to lack of efficacy in the placebo group than in the etoricoxib and naproxen group (25.2%, 12.5%, 10.5%, respectively, p\<0.001 vs placebo). The results of all patients who had at least one post-randomization efficacy measurement were included in the primary analysis of efficacy (93.0% in the placebo group, 97.5% in the etoricoxib group and 96.1% in the naproxen group). <figure> <p><img src="" /></p> <figcaption>Study flowchart. AE = adverse event. "Discontinued due to other reasons" = patient lost to follow-up, moved, withdrew consent, protocol deviation, study site terminated.</figcaption> </figure> ::::table-wrap

::: caption
Baseline patient characteristics
:::

**Characteristic** **Placebo** **Etoricoxib 90 mg** **Naproxen 1000 mg**

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```
                                                                                         **(N = 357)**   **(N = 353)**          **(N = 181)**
```

% women 82 81 82
Mean age [yrs] (SD) 52 (12) 53 (12) 52 (12)
Mean duration of rheumatoid arthritis [yrs] (SD) 9 (8) 8 (8) 8 (8)
% rheumatoid factor-positive 83 85 87
% in ARA functional class:\
I 27 31 27
II 56 53 58
III 17 16 16
% taking rheumatoid arthritis medications:\
Corticosteroids 57 54 59
Disease modifying antirheumatic drugs 83 83 81
Methotrexate 59 55 62
Mean patient global assessment of disease activity (100 mm visual analog scale) ^‡^ (SD) 65 (19) 66 (20) 65 (19)
Mean investigator global assessment of disease activity (0 to 4 scale) ^‡^ (SD) 2.7 (0.6) 2.7 (0.7) 2.7 (0.6)
Mean number of tender joints (of 68) ^‡^ (SD) 29 (15) 29 (15) 28 (15)
Mean number of swollen joints (of 66) ^‡^ (SD) 19 (12) 19 (13) 18 (12)

^‡^ Higher score corresponds to greater disease activity.:::: 

## Efficacy Table [2](#) summarizes the results of the treatment comparisons for the primary and secondary efficacy endpoints. For all 4 primary endpoints, etoricoxib and naproxen were statistically superior to placebo. For all secondary endpoints, except serum C-reactive protein, both etoricoxib and naproxen were also superior to placebo. Serum C-reactive protein levels increased on etoricoxib compared to placebo. This was not seen in the naproxen group. There was no significant difference between etoricoxib and naproxen for any of the primary or secondary endpoints. The percentage of patients who achieved ACR20 responder criteria response was 40.9% in the placebo group, 58.7% in the etoricoxib group, and 57.5% in the naproxen group. Treatment effects of etoricoxib were rapid, occurring at the earliest time point measured (week 2), and were maintained over the entire 12-week study period (Figures [2a,2b,2c,2d](#)). Treatment effects of etoricoxib were consistent across corticosteroid users and non-users. <figure> <p><img src="" /></p> <figcaption>Changes from baseline on primary endpoints: a) tender joint counts; b) swollen joint counts; c) patient global assessments of disease activity; d) investigator global assessments of disease activity. S = screening visit, R = randomization (baseline) visit; SE = standard error. Screening (S) to randomization (R) = washout period for prior NSAID therapy. Empty circle = placebo, empty triangle = etoricoxib 90 mg, solid diamond = naproxen 1000 mg. A last-observation-carried-forward approach was used for missing values.</figcaption> </figure> ::::table-wrap
::: caption
Mean (95% confidence interval) efficacy differences between treatments
over 12 weeks
:::

```
                                                                  **Etoricoxib vs placebo**   **Naproxen vs placebo**   **Etoricoxib vs naproxen**
```

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**Primary endpoints**\
Patient global assessment of disease activity (100 mmVAS) ‡ -9.93^*^ (-12.96, -10.0^*^ (-13.7, 0.09 (-3.61, 3.79)
-6.90) -6.32)\
Investigator global assessment of disease activity (0--4 scale) ‡ -0.43^*^ (-0.55, -0.51^*^ (-0.66, 0.08 (-0.08, 0.24)
-0.30) -0.35)\
Tender joint count (total 68 joints) ‡ -3.42^*^ (-4.89, -3.16^*^ (-4.96, -0.26 (-2.05, 1.54)
-1.94) -1.36)\
Swollen joint count (total 66 joints) ‡ -1.43† (-2.42, -1.39† (-2.60, -0.03 (-1.24, 1.17)
-0.44) -0.19)\
**Secondary endpoints**\
Patient global assessment of pain (100 mm VAS) ‡ -9.62^*^ (-12.73, -10.46^*^ (-14.25, 0.84 (-2.96, 4.63)
-6.51) -6.66)\
Health Assessment Questionnaire disability (0--3 scale) ‡ -0.20^*^ (-0.28, -0.29^*^ (-0.38, 0.08 (0.00, 0.17)
-0.13) -0.20)\
Serum C-reactive protein (ratio between treatments) 1.11† (1.00, 1.23) 0.99 (0.87, 1.13) 1.12 (0.99, 1.27)
ACR20 responder criteria (%) 17.83^*^ (10.55, 25.12) 16.68^*^ (7.80, 25.57) 1.15 (-7.74, 10.03)
Discontinuation due to lack of efficacy (%) -12.75^*^ (-18.42, -14.71^*^ (-21.06, 1.97 (-3.67, 7.61)
-7.07) -8.37)

Note: Negative values indicate improvement except for ACR20 responder
criteria and serum C-reactive protein.

^\*^ The difference vs placebo was significant (p\<0.001). † The
difference vs placebo was significant (p\<0.05). ‡ For these measures,
the difference shown is for the least squares mean of the time-weighted
average change from baseline over 12 weeks. ACR20 responder criteria and
Discontinuations due to lack of efficacy are shown as differences in
frequency over the 12-week period. Serum C-reactive protein was
calculated as a ratio between treatments over the 12-week treatment
period.:::: 

## Tolerability The adverse event rates for the 3 treatment groups are summarized in Table [3](#). Clinical adverse events determined by the investigator as possibly, probably, or definitely drug-related occurred in 15.4%, 23.2%, and 19.3% of patients in the placebo, etoricoxib 90 mg, and naproxen 500 mg twice daily groups (p\<0.05 for etoricoxib versus placebo). There was no individual drug-related adverse event that was predominantly responsible for the difference between etoricoxib and placebo; in fact, there were no individual drug-related adverse events with an incidence ≥4% in any treatment group. The active treatments were not significantly different from placebo (p>0.05) with regard to the percentages of patients with any serious clinical adverse event or who discontinued due to a clinical adverse event (Table [3](#)). Only 3 of the serious clinical adverse events were judged to be drug-related by the investigators: 2 on etoricoxib (duodenal ulcer and hip pain) and 1 on naproxen (hypertension). There were no deaths reported. No clinically relevant trends were noted in the overall incidence of laboratory adverse events or mean changes in alanine aminotransferase, aspartate aminotransferase, serum creatinine, and hemoglobin plus hematocrit. ::::table-wrap
::: caption
Summary of safety data
:::

```
                                              **Placebo**     **Etoricoxib 90 mg**   **Naproxen 1000 mg**
```

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```
                                              **(N = 357)**   **(N = 353)**          **(N = 181)**
                                              n (%)           n (%)                  n (%)
```

**Number of patients:**\
With any drug-related clinical adverse event 55 (15.4) 82 (23.2) ^†^ 35 (19.3)
With any serious clinical adverse event ^‡^ 3 (0.8) 7 (2.0) 3 (1.7)
Discontinued due to clinical adverse event 6 (1.7) 9 (2.5) 5 (2.8)

^†^ p < 0.05 vs placebo.

^‡^ Serious adverse events were: placebo (3 patients) --
thrombophlebitis, atrial fibrillation, and pneumothorax; etoricoxib (7
patients) -- pulmonary embolism, angina pectoris, thyroid cancer,
duodenal ulcer, hip pain, femoral fracture, and traumatic arthropathy
plus corneal degeneration (in the same patient); naproxen (3 patients)
-- hypertension, intervertebral disc displacement, and retinal
detachment.:::: The most commonly reported adverse events, those with an incidence of ≥3% in any treatment group, are summarized in Table [ 4](#). Events of special interest in evaluating COX inhibitors are also summarized in Table [4](#). The incidence of gastrointestinal nuisance symptoms was similar among all treatment groups (10.1%, 10.8%, and 11.6% in the placebo, etoricoxib and naproxen groups, respectively). The incidence of lower extremity edema adverse events in the study was low and similar among treatment groups. No patients discontinued due to lower extremity edema. Although there was an increase in hypertension adverse events in patients taking etoricoxib and naproxen versus placebo, discontinuations due to hypertension adverse events were rare (1 patient on naproxen). Over 12 weeks, mean systolic blood pressures decreased slightly from baseline in the placebo group, and increased slightly in the etoricoxib and naproxen groups (the maximum difference between means at any time point was \<3.5 mm Hg for etoricoxib and \<2 mm Hg for naproxen) (Figure [3](#)). Mean diastolic blood pressures did not change substantially from baseline values in any treatment group during the study (the maximum difference at any time point was ≤1.1 mm Hg). There was only 1 confirmed duodenal ulcer in the study (in the etoricoxib treatment group). There were 3 confirmed cardiovascular thrombotic adverse events: 2 on etoricoxib (angina pectoris and pulmonary embolism) and 1 on placebo (thrombophlebitis). <figure> <p><img src="" /></p> <figcaption>Mean changes from baseline in systolic blood pressure (mm Hg). S = screening visit, R = randomization (baseline) visit; SE = standard error. Screening (S) to randomization (R) = washout period for prior NSAID therapy. Empty circle = placebo, empty triangle = etoricoxib 90 mg, solid diamond = naproxen 1000 mg.</figcaption> </figure> ::::table-wrap
::: caption
Most common adverse events and events of interest in evaluating
COX-inhibitors
:::

```
                                                    **Placebo**     **Etoricoxib 90 mg**   **Naproxen 1000 mg**
```

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```
                                                    **(N = 357)**   **(N = 353)**          **(N = 181)**
                                                    n (%)           n (%)                  n (%)
```

**Most Common Adverse Events†**\
Headache 20 (5.6) 24 (6.8) 6 (3.3)
Hypertension 5 (1.4) 12 (3.4) 5 (2.8)
Upper Respiratory Infection 11 (3.1) 8 (2.3) 8 (4.4)
Urinary Tract Infection 16 (4.5) 15 (4.2) 8 (4.4)
**Events of Interest in Evaluating COX Inhibitors**\
**Gastrointestinal (GI) Adverse Events**\
GI Nuisance Symptoms ^‡^ 36 (10.1) 38 (10.8) 21 (11.6)
Discontinuations 2 (0.6) 2 (0.6) 2 (1.1)
**Renovascular Adverse Events**\
Lower Extremity Edema (LEE) 3 (0.8) 3 (0.8) 2 (1.1)
Discontinuations due to LEE 0 (0.0) 0 (0.0) 0 (0.0)
Congestive Heart Failure 0 (0.0) 0 (0.0) 0 (0.0)
Hypertension 5 (1.4) 12 (3.4) 5 (2.8)
Discontinuations due to hypertension 0 (0.0) 0 (0.0) 1 (0.6)

† Incidence ≥ 3% in any treatment group.

‡ Includes abdominal pain, acid reflux, dyspepsia, epigastric
discomfort, heartburn, nausea, and vomiting.::::


Extracted trial result:
Outcome: ACR20 responder criteria (continuous)
Intervention: naproxen 500 mg twice daily
Comparator: placebo
Intervention group size: 181
Comparator group size: 357
Notes: found in table 2, but differences given rather than raw values. Also ranges provided rather than STD, cannot calculate