A Two-Part 26-Week Study of Etoricoxib as Treatment for Ankylosing Spondylitis (AS) (MK-0663-108)

Study Overview
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Brief Summary
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The purpose of the study is to evaluate the efficacy and tolerability of two doses of etoricoxib compared to naproxen in the treatment of ankylosing spondylitis (AS). The primary objectives are to evaluate the improvement in Spinal Pain Intensity over 6 weeks of treatment with etoricoxib 90 mg or 60 mg compared to naproxen; and to evaluate the improvement in Spinal Pain Intensity over 6 weeks of treatment with etoricoxib 90 mg compared with etoricoxib 60 mg. Additionally the added benefit of increasing the dose of etoricoxib from 60 mg to 90 mg will be assessed in the second part of the study. The primary hypothesis is that the improvement in Spinal Pain Intensity visual analog scale (VAS) as measured by the time-weighted average (TWA) change from baseline over 6 weeks of treatment in Part I for etoricoxib 90 mg or 60 mg once daily is not inferior to naproxen 1000 mg.

Official Title
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A Phase III, Two-Part, Randomized, Double-Blind, Active Comparator-Controlled, Multicenter Clinical Trial to Study the Relative Efficacy and Tolerability of Two Doses of MK-0663/Etoricoxib in Patients With Ankylosing Spondylitis

Conditions
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Spondylitis, Ankylosing

Intervention / Treatment
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* Drug: Part I - etoricoxib 60 mg
* Drug: Part I - etoricoxib 90 mg
* Drug: Part I- naproxen 1000 mg
* Drug: Part I - Placebo to naproxen 500 mg
* Drug: Part II- etoricoxib 60 mg
* Drug: Part II- etoricoxib 90 mg
* Drug: Part II- naproxen 1000 mg
* Drug: Part I - Placebo to etoricoxib 60 mg
* Drug: Part I - Placebo to etoricoxib 90 mg
* Drug: Part II- Placebo to etoricoxib 60 mg
* Drug: Part II - Placebo to etoricoxib 90 mg
* Drug: Part II- Placebo to naproxen 500 mg


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Has a definite diagnosis of Ankylosing Spondylitis (AS) per Modified New York Criteria made at least 6 months prior to screening Has a history of positive therapeutic benefit with non-steroidal anti-inflammatory drugs (NSAIDs) and regular use of NSAIDS for past 30 days Has a score on Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) Question 2 at screening visit that is <77 mm Must demonstrate sufficient flare or worsening of AS pain Is in general good health (other than AS) Has had approved non-study antirheumatic therapy that has been at stable dosing AND is not anticipated to undergo a change within the first 6 weeks of the protocol Exclusion Criteria: Has inflammatory arthritis (eg, rheumatoid arthritis, psoriatic arthritis, crystal-induced arthritis, spondyloarthropathy, diffuse idiopathic skeletal hyperostosis [DISH]), polymyalgia rheumatica, a history of septic arthritis or intra-articular fracture of the study joint, Wilson's disease, hemachromatosis, ochronosis, or primary osteochondromatosis Has acute peripheral articular disease (onset within 4 weeks prior to screening) of an active (painful or swollen) peripheral arthritis Has a history of gastric or biliary surgery, or small intestine surgery that causes clinical malabsorption Has had an active peptic (gastric or duodenal) ulcer or history of inflammatory bowel disease Has undergone coronary artery bypass graft surgery (CABG), angioplasty, or has a cerebrovascular accident or transient ischemic attack within the past 6 months or has active ischemic heart disease, cerebrovascular disease, or peripheral vascular disease Has Class II-IV congestive heart failure Has uncontrolled hypertension Has a history of neoplastic disease, except adequately treated basal cell carcinoma or carcinoma in situ of the cervix, or malignancies that have been successfully treated ≥ 5 years prior to screening Has history of leukemia, lymphoma, malignant melanoma, and myeloproliferative disease Allergy to etoricoxib or naproxen, or history of a significant clinical or laboratory adverse experience associated with etoricoxib or naproxen Has a history or family history of an inherited or acquired bleeding disorder Is considered morbidly obese and demonstrates significant health problems stemming from obesity, which would confound study participation or interpretation of study results Is pregnant, breast-feeding, or expecting to conceive during the study Has a clinical diagnosis of hepatic insufficiency defined as Child-Pugh score ≥ 5

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: etoricoxib 60 mg/etoricoxib 60 mg<br>The etoricoxib 60 mg/etoricoxib 60 mg treatment sequence will receive etoricoxib 60 mg in Part I and Part II | Drug: Part I - etoricoxib 60 mg<br>* etoricoxib 60 mg oral tablet once daily for 6 weeks<br>* Other names: MK-0663;Drug: Part I - Placebo to naproxen 500 mg<br>* Placebo to naproxen 500 mg oral tablet twice daily for 6 weeks<br>Drug: Part II- etoricoxib 60 mg<br>* etoricoxib 60 mg oral tablet once daily for 20 weeks<br>* Other names: MK-0663;Drug: Part I - Placebo to etoricoxib 90 mg<br>* Placebo to etoricoxib 90 mg oral tablet once daily for 6 weeks.<br>Drug: Part II - Placebo to etoricoxib 90 mg<br>* Placebo to etoricoxib 90 mg oral tablet once daily for 20 weeks.<br>Drug: Part II- Placebo to naproxen 500 mg<br>* Placebo to naproxen 500 mg orally twice daily for 20 weeks.<br>|
| Experimental: etoricoxib 60 mg/etoricoxib 90 mg<br>The etoricoxib 60 mg/etoricoxib 90 mg treatment sequence will receive etoricoxib 60 mg in Part I and etoricoxib 90 mg in Part II | Drug: Part I - etoricoxib 60 mg<br>* etoricoxib 60 mg oral tablet once daily for 6 weeks<br>* Other names: MK-0663;Drug: Part I - Placebo to naproxen 500 mg<br>* Placebo to naproxen 500 mg oral tablet twice daily for 6 weeks<br>Drug: Part II- etoricoxib 90 mg<br>* etoricoxib 90 mg oral tablet once daily for 20 weeks<br>* Other names: MK-0663;Drug: Part I - Placebo to etoricoxib 90 mg<br>* Placebo to etoricoxib 90 mg oral tablet once daily for 6 weeks.<br>Drug: Part II- Placebo to etoricoxib 60 mg<br>* Placebo to etoricoxib 60 mg oral tablet once daily for 20 weeks.<br>Drug: Part II- Placebo to naproxen 500 mg<br>* Placebo to naproxen 500 mg orally twice daily for 20 weeks.<br>|
| Experimental: etoricoxib 90 mg/etoricoxib 90 mg<br>The etoricoxib 90 mg/etoricoxib 90 mg treatment sequence will receive etoricoxib 90 mg in Part I and Part II | Drug: Part I - etoricoxib 90 mg<br>* etoricoxib 90 mg oral tablet once daily for 6 weeks<br>* Other names: Mk-0663;Drug: Part I - Placebo to naproxen 500 mg<br>* Placebo to naproxen 500 mg oral tablet twice daily for 6 weeks<br>Drug: Part II- etoricoxib 90 mg<br>* etoricoxib 90 mg oral tablet once daily for 20 weeks<br>* Other names: MK-0663;Drug: Part I - Placebo to etoricoxib 60 mg<br>* Placebo to etoricoxib 60 mg oral tablet once daily for 6 weeks.<br>Drug: Part II- Placebo to etoricoxib 60 mg<br>* Placebo to etoricoxib 60 mg oral tablet once daily for 20 weeks.<br>Drug: Part II- Placebo to naproxen 500 mg<br>* Placebo to naproxen 500 mg orally twice daily for 20 weeks.<br>|
| Active Comparator: naproxen 1000 mg/naproxen 1000 mg<br>The naproxen 1000 mg/naproxen 1000 mg treatment sequence will receive naproxen 1000 mg in Part I and Part II | Drug: Part I- naproxen 1000 mg<br>* naproxen 500 mg oral tablet twice daily for 6 weeks<br>Drug: Part II- naproxen 1000 mg<br>* naproxen 500 mg oral tablet twice daily for 20 weeks<br>Drug: Part I - Placebo to etoricoxib 60 mg<br>* Placebo to etoricoxib 60 mg oral tablet once daily for 6 weeks.<br>Drug: Part I - Placebo to etoricoxib 90 mg<br>* Placebo to etoricoxib 90 mg oral tablet once daily for 6 weeks.<br>Drug: Part II- Placebo to etoricoxib 60 mg<br>* Placebo to etoricoxib 60 mg oral tablet once daily for 20 weeks.<br>Drug: Part II - Placebo to etoricoxib 90 mg<br>* Placebo to etoricoxib 90 mg oral tablet once daily for 20 weeks.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time-Weighted Average Change From Baseline in the Spinal Pain Intensity in Study Part 1: Etoricoxib 90 mg vs. Naproxen | Spinal Pain Intensity is measured using a visual analog scale (VAS) from 0-100 mm with a lower value representing a better response. The time-weighted average change is calculated by taking the time between adjacent observations divided by the time from the randomization visit to the last observation in the period of interest, and using it as the weight for computation of the average. | Baseline and up to Week 6 | 
| Time-Weighted Average Change From Baseline in the Spinal Pain Intensity in Study Part 1: Etoricoxib 60 mg vs. Naproxen | Spinal Pain Intensity is measured using a visual analog scale (VAS) from 0-100 mm with a lower value representing a better response. The time-weighted average change is calculated by taking the time between adjacent observations divided by the time from the randomization visit to the last observation in the period of interest, and using it as the weight for computation of the average. | Baseline and up to Week 6 | 
| Number of Participants Discontinuing Study Treatment Due to an Adverse Event |  | Up to 26 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time-Weighted Average Change From Baseline in the Spinal Pain Intensity in Study Part 1: Etoricoxib 90 mg vs. Etoricoxib 60 mg | Spinal Pain Intensity is measured using a visual analog scale (VAS) from 0-100 mm with a lower value representing a better response. The time-weighted average change is calculated by taking the time between adjacent observations divided by the time from the randomization visit to the last observation in the period of interest, and using it as the weight for computation of the average. | Baseline and up to Week 6 | 
| Average Change From Week 6 in the Spinal Pain Intensity Over Weeks 10 and 12 in Study Part 2: Etoricoxib 60/90 mg vs. Etoricoxib 60mg (Non-responders From Part I) | Spinal Pain Intensity is measured using a visual analog scale (VAS) from 0-100 mm with a lower value representing a better response. Average change from Week 6 in Spinal Pain Intensity (VAS) over Weeks 10 and 12 is calculated as the average Spinal pain Intensity (VAS) value over Weeks 10 and 12 minus the Spinal Pain Intensity (VAS) at Week 6. | Week 6 to Week 10 and Week 12 |