The relative efficacy and tolerability of two doses of etoricoxib versus naproxen in patients with ankylosing spondylitis: a randomized, clinical trial

• Both doses of etoricoxib (60 and 90 mg) were non-inferior to naproxen
• Etoricoxib 60 and 90 mg effectively control pain in patients with ankylosing spondylitis (AS); however, 60 mg once daily seem to be the lowest effective dose for most patients

Ankylosing spondylitis is a very common disease mainly causing chronic inflammation of the spine and spinal pain, typically at night and upon awakening. The frequent chronic pain significantly impairs the patients’ quality of life, thereby affecting the psychological well-being in addition to their physical disability. Non-steroidal anti-inflammatory drugs (NSAIDs) are known to be the first line agents prescribed for the treatment of AS. Nowadays, various biologic therapies are avaiable for AS and have shown significant improvements in inflammatory burden and the functional ability. However, NSAIDs have also confirmed the prominent treatment benefits for AS patients. The mechanism of NSAIDs involves the inhibiting the synthesis of prostaglandin through inhibition of the enzyme cyclooxygenase (COX). Prostaglandin E2 (PGE2) promotes osteoclast activity and stimulates osteoblast activity and in AS patients which is responsible for causing new pathologic bone formation. Previous research has shown that NSAIDs can slow radiographic progression in AS patients and may be more marked with COX-2 selective NSAIDs, although such findings could not be confirmed. Etoricoxib, a COX-2 selective NSAID has demonstrated the therapeutic benefit in AS and also in other acute and chronic pain conditions.

Rationale behind research:

• Previous studies have demonstrated that NSAIDs can slow radiographic progression in AS patients and may be more pronounced with COX-2 selective NSAIDs, although such findings could not be confirmed in all studies.
• This study assessed the dose related efficacy and safety/tolerability profile of etoricoxib in patients with AS by comparing etoricoxib 60 mg with naproxen 1000 and 90 mg with naproxen 1000 mg over 6 weeks and evaluating the potential benefit of increasing the etoricoxib dose to 90 mg in patients with inadequate pain responses to 60 mg.

Objective:

To evaluate the two doses of etoricoxib (60 and 90 mg) vs. naproxen 1000 mg in subjects with ankylosing spondylitis.

Study outcomes

Primary outcomes: The primary endpoint of this study was the time weighted average change from baseline in SPI (100-mm VAS) over 6 weeks. The primary hypotheses according to the primary endpoint were that etoricoxib 90 mg once daily is not inferior to naproxen 1000 mg and that etoricoxib 60 mg once daily is not inferior to naproxen 1000 mg. The Per Protocol Population was used to assess the primary endpoint.

Secondary outcomes: Key secondary endpoints included time weighted average change from baseline in SPI (VAS) in Part I (etoricoxib 90 mg vs. etoricoxib 60 mg; using the Modified Intention to Treat population (mITT) and average change from week 6 in SPI (VAS) over the average of weeks 10 and 12 among inadequate responders to etoricoxib 60 mg (inadequate responder defined as a subject with 50% improvement from baseline in SPI (VAS) at week 6. Other Secondary Endpoints included time  -weighted average change from baseline in SPI (VAS) over 26 weeks, time weighted average response in Patient Global Assessment of Response to Therapy (PGART; Likert) over 6 weeks, proportion of patients who discontinue due to lack of efficacy over 6 weeks. Average change from week 6 in PGART (Likert) over weeks 10 and 12, and change from baseline in SPI (VAS) at each week of the study. Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) composite score (VAS) and the morning stiffness duration and severity was also evaluated.

Time points: Part 1: Baseline and weeks 2,4, 6 Part 11: Baseline and weeks 10.12, 18, 26

Outcomes:

Baseline: Baseline demographics were similar among the treatment groups. 

Primary Outcomes: For the primary endpoint of the time weighted average change from baseline SPI score over 6 weeks of treatment in Part I, results were similar between the etoricoxib 60 mg, etoricoxib 90 mg, and naproxen 1000 mg groups. For the comparison of etoricoxib 90 mg vs. 60 mg, the time weighted average change from baseline SPI score was numerically greater for the etoricoxib 90 mg group as compared to the etoricoxib 60 mg group over 6 weeks of treatment. However, this difference did not achieve statistical significance at the pre-specified critical alpha=0.20 (p=0.396). The time-weighted average response PGART score was similar between the etoricoxib 60 mg, etoricoxib 90 mg, and naproxen 1000 mg groups over 6 weeks of treatment in Part I.

Figure 1: Time-weighted LS Mean Change from Baseline in Spinal Pain Intensity

Secondary Outcomes: In patients considered inadequate responders to etoricoxib 60 mg in Part I, the average change from week 6 over the average of weeks 10 and 12 in SPI score was statistically significantly better (at critical alpha=0.20) in the group of inadequate responders who switched to etoricoxib 90 mg (n=178) versus the group of inadequate responders who remained on etoricoxib 60 mg (n=175) (p=0.112).

The time-weighted average change from baseline SPI score was similar between the etoricoxib 60 mg/60 mg, etoricoxib 90 mg/90 mg, and naproxen 1000 mg/1000 mg groups over 26 weeks of treatment in the study. The average change from week 6 over weeks 10 and 12 in PGART score was similar between the group of inadequate responders who remained on etoricoxib 60 mg and the group of inadequate responders who switched to etoricoxib 90 mg. For the measure of time weighted LS Mean change from baseline in the BASDAI score, etoricoxib 90 mg had the greatest change from baseline by the end of Part I. However, the nominal p-value for the 90 mg dose vs. naproxen was 0.425; nominal p-value for the 60 mg dose vs. naproxen was 0.866. Results for the severity and the duration of morning stiffness demonstrated a stronger numerical dose-related trend; however, nominal p-values for etoricoxib 90 mg vs. naproxen were 0.119 for duration and 0.131 for severity and for etoricoxib 60 mg vs. naproxen, nominal p-values were 0.483 for duration and 0.627 for severity.

In this study, both etoricoxib 90 and 60 mg were noninferior to naproxen 1000 mg on the primary endpoint of time weighted average change from baseline in the SPI score of a 6 week period. These results were further validated by other endpoints, including PGART and discontinuations due to lack of efficacy. An analysis was done for the secondary objective comparing the effect of etoricoxib 90 mg vs. etoricoxib 60 mg on the timeweighted average change from baseline SPI score; the difference in the effect did not meet the prespecified MCID.

Among the subset of patients who did not have an adequate response to the 60 mg dose in Part I, those who received the 90 mg dose in Part II demonstrated an additional average improvement of ~3 mm in SPI score from week 6 over weeks 10 and 12 as compared to patients who continued receiving the 60 mg dose in Part II. This result was identified as being statistically significant in this study; however, the results were not supported by PGART results. There were no significant differences in adverse events between treatment groups. Though a small numeric increase in serious adverse events was noted in Part II in 90 and 60 mg/90 mg treatment arms as compared to 60 mg treatment arm. Previous analyses have suggested that NSAIDs, including COX-2 selective agents such as etoricoxib, have a similar increased risk of cardiovascular (CV) events, although with the possible exception of naproxen which is not associated with an increased risk. A large outcome program (the MEDAL program) demonstrated a similar rate of thrombotic CV events with etoricoxib (60 or 90 mg) and diclofenac 150 mg; the MEDAL program also demonstrated a reduced risk of uncomplicated upper gastrointestinal events with etoricoxib vs. diclofenac.