Barkhuizen 2006.

Methods	Design: RCT Number of centres: NA Treatment duration: 12 weeks Flare design: Yes Wash‐out period: Yes (analgesics for 8 hours and anti‐inflammatory medication for 72 hours) Time point of assessments: Screening, BL, 1, 3, 6 and 12 weeks, at discontinuation
Participants	Inclusion criteria: 1. Age 18 to 75; 2. AS with axial involvement; 3. Requiring daily treatment with NSAIDs during the previous 30 days; 4. Pain intensity ≥ 50mm on VAS, worsening by 30% after discontinuation therapy between pre‐inclusion visit and inclusion; 5. No analgesic use for at least 8 hours or anti‐inflammatory medication use for at least 72 hours prior to study start; 6. Negative pregnancy‐test at inclusion and on contraception throughout trial. Exclusion criteria: 1. Distal small‐joint synovitis; 2. Inflammatory enteropathy; 3. Extra‐articular signs; 4. Vertebral compression; 5. Needing to wear a corset during the trial; 6. Requiring physiotherapy or re‐education or manipulation during the trial; 7. Requiring concomitant use of muscle relaxants, hypnotics, anxiolytics, sedatives, tranquillizers, anticoagulants, ticlopidine, or lithium; 8. Use of antidepressants (unless taking stable dose for 2 weeks prior to inclusion); 9. Corticosteroids in 6 weeks prior to study start; 10. Receving MTX > 25 mg/week or anti‐TNF agents (SSZ only when taking stable dose for 60 days prior to screening); 11. History of gastroduodenal ulcer confirmed by endoscopy in 30 days prior to inclusion or with concurrent gastrointestinal bleeding; 12. Known hypersensitivity to analgesics, NSAIDs, celecoxib, COX‐2‐selective inhibitors, naproxen, lactose, sulfonamide, or APAP; 13. History of asthma, chronic disease that might interfere with study results or current/previous malignancy. Classification: modified New York criteria Celecoxib (200 mg): Number of participants: 137 Number of completers: 100 Age (mean (SD)): 43.9 (11.9) Male (%): 79 Symptom duration: NA Disease duration: NA HLA‐B27 positive (%): NA Celecoxib (400 mg): Number of participants: 161 Number of completers: 118 Age (mean (SD)): 45.1 (11.6) Male (%): 70 Symptom duration: NA Disease duration: NA HLA‐B27 positive (%): NA Naproxen (500 mg): Number of participants: 157 Number of completers: 118 Age (mean (SD)): 45.4 (12.6) Male (%): 75 Symptom duration: NA Disease duration: NA HLA‐B27 positive (%): NA Placebo: Number of participants: 156 Number of completers: 72 Age (mean (SD)): 43.8 (11.5) Male (%): 73 Symptom duration: NA Disease duration: NA HLA‐B27 positive (%): NA
Interventions	Celecoxib (200 mg) vs Celexocib (400 mg) vs Naproxen (500 mg) vs Placebo Co‐medication: Rescue APAP as needed (max 2000 mg/day), stable dose SSZ, MTX < 25 mg/week, or stable dose antidepressants, or both
Outcomes	Extracted outcomes: 1. Withdrawals due to adverse events 2. BASDAI (mean change after 12 weeks) (scale 0 to 100, higher is worse) Celecoxib 200 mg: ‐15.4 (N = 137) Celecoxib 400 mg: ‐19.5 (N = 161) Naproxen 500 mg: ‐22.9 (N = 157) Placebo: ‐1.74 (N = 156) 3. Duration of morning stiffness (median change after 12 weeks) (in minutes, higher is worse) Celecoxib 200 mg: ‐5 (N = 137) (P < 0.05 all treatment groups versus placebo) Celecoxib 400 mg: ‐20 (N = 161) Naproxen 500 mg: ‐30 (N = 157) (P < 0.05 versus celecoxib 200 mg) Placebo: 0 (N = 156) 4. CRP (mean change after 12 weeks) (in mg/L, higher is worse) Celecoxib 200 mg: ‐2.46 (N = 137) (P < 0.05 all treatment groups versus placebo) Celecoxib 400 mg: ‐2.64 (N = 161) Naproxen 500 mg: ‐3.60 (N = 157) Placebo: +1.17 (N = 156) 5. ASAS 20 6. Number of any adverse events 7. Number of serious adverse events 8. Number of adverse events per organ system
Notes	The outcomes pain on VAS, patient's global assessment of disease activity and BASFI were also presented, but these data could not be used due to presentation in graphs from which the data could not be extracted. Outcomes that were not included in the meta‐analysis, because no measure of variance (SD, SE or CI) was reported for these outcomes: BASDAI, duration of morning stiffness, CRP. Available results are described in this table. In comparison 1 (NSAID vs NSAID), comparison 4 (COX‐2 vs Placebo), comparison 5 (COX‐2 vs traditional NSAID) and comparison 6 (Naproxen vs other NSAID) we chose to present data from Celecoxib 400 mg instead of Celecoxib 200 mg (see Measures of treatment effect for rationale). Funding source: Pfizer
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	"Patients were randomized to receive either…". Probably done, but no further information was provided.
Allocation concealment (selection bias)	Unclear risk	No information provided on allocation concealment.
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	"double‐blind, placebo‐controlled". Probably done, but no further information was provided on blinding of participants.
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	"double‐blind". Probably done, but no further information was provided on blinding of outcome assessor.
Incomplete outcome data (attrition bias) All outcomes	Low risk	"All efficacy analyses were performed on data from the intent‐to‐treat population cohort, defined as patients who were randomized to treatment and took at least one dose of study medication"; "In total, 408 (67%) patients completed the study: 72 (46%) in the placebo group, 100 (73%) in the celecoxib 200mg group, 188 (73%) in the celecoxib 400mg group, and 118 (75%) in the naproxen group. The most common reason for withdrawal was lack of efficacy, with a higher proportion of patients in the placebo group (38%) withdrawing for this reason than in the celecoxib 200 mg (18%) , celecoxib 400 mg (14%), or naproxen (11%) groups."
Selective reporting (reporting bias)	Low risk	All outcomes that would be reported according to the methods section, are reported in the results section.
Other bias	Low risk	Sufficient power for primary efficacy hypothesis (sample size calculations). No different co‐interventions between groups, other than "rescue" acetaminophen.