A Two-Part, 12-Week Study of Etoricoxib as a Treatment for Rheumatoid Arthritis (RA) (MK-0663-107)

Study Overview
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Brief Summary
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This is a 2-part (6 weeks duration for each part), randomized, double-blind, placebo-controlled study in participants with rheumatoid arthritis. The hypothesis is that etoricoxib (60 mg and 90 mg) administration will demonstrate superior efficacy compared to placebo after 6 weeks of treatment, as measured by the greater mean improvement from baseline in the Disease Activity Score C-Reactive Protein (DAS-28 CRP), and by the greater mean improvement in Patient Global Assessment of Pain (PGAP) from baseline over 6 weeks of treatment. 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.

Official Title
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A Phase III, Two-Part, Randomized, Double-Blind, Placebo-Controlled, Multicenter Clinical Trial to Assess the Relative Efficacy and Tolerability of Two Doses of MK-0663/Etoricoxib in Patients With Rheumatoid Arthritis

Conditions
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Arthritis, Rheumatoid

Intervention / Treatment
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* Drug: Etoricoxib 60 mg
* Drug: Etoricoxib 90 mg
* Drug: Placebo to Etoricoxib 60 mg
* Drug: Placebo to Etoricoxib 90 mg


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Is male or female ≥ 18 years of age in general good health (other than RA) Has an American College of Rheumatology Rheumatoid Clinical Response Criteria (ACR) Functional Class I, II, or III Has a diagnosis of RA at least 6 months ago and was at least 16 years of age when diagnosed Has a history of positive therapeutic benefit with nonsteroidal anti-inflammatory drugs (NSAIDs) and is taking an NSAID on a regular basis and at a therapeutic dose level and is not anticipated to undergo a change during the study Exclusion Criteria: Has a concurrent medical/arthritic disease that could confound or interfere with evaluation of efficacy Has a history of gastric or biliary surgery (including gastric bypass surgery) or small intestine surgery that causes clinical malabsorption Has an active peptic (gastric or duodenal) ulcer or history of inflammatory bowel disease Has a confirmed medical diagnosis of ischemic heart disease, cerebrovascular disease, or peripheral artery occlusive disease Class II-IV congestive heart failure Has uncontrolled hypertension (systolic >160 mm Hg or diastolic > 90 mm Hg) at Visit 1 or Visit 2 Has a clinical diagnosis of hepatic insufficiency defined as Child-Pugh score ≥5 Has estimated glomerular filtration rate ≤30 mL/min Has a history of neoplastic disease within 5 years (exceptions: basal cell carcinoma or carcinoma in situ of the cervix) Is allergic to etoricoxib; history of a significant clinical or laboratory adverse experience associated with etoricoxib; hypersensitivity to aspirin or NSAIDs; or allergy to acetaminophen/paracetamol Has a personal or family history of an inherited or acquired bleeding disorder Requires oral corticosteroid therapy in excess of the equivalent of 10 mg daily of prednisone and/or have not been on a stable dose for at least 4 weeks prior to Visit 1 and/or whose dose is not expected to remain stable during the study Treated with B-cell depleting therapies within the past 6 months or anticipate this treatment during this trial Is a recreational or illicit drug use, or history within 5 years of drug or alcohol abuse/dependence; Is morbidly obese (defined as body mass index ≥40 kg/m^2) Is pregnant or breast feeding

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 tablets administered orally once daily for 6 weeks in Part 1 and Part 2 of the study. | Drug: Etoricoxib 60 mg<br>* One tablet orally once daily for 6 weeks.<br>* Other names: MK-0663;Drug: Placebo to Etoricoxib 60 mg<br>* One tablet orally once daily for 6 weeks.<br>|
| Experimental: Etoricoxib 60 mg/Etoricoxib 90 mg<br>The etoricoxib 60 mg/etoricoxib 90 mg treatment sequence will receive etoricoxib 60 mg tablets administered orally once daily for 6 weeks in Part 1 and etoricoxib 90 mg tablets administered orally once daily for 6 weeks in Part 2 of the study. | Drug: Etoricoxib 60 mg<br>* One tablet orally once daily for 6 weeks.<br>* Other names: MK-0663;Drug: Placebo to Etoricoxib 60 mg<br>* One tablet orally once daily for 6 weeks.<br>|
| Experimental: Etoricoxib 90 mg<br>The etoricoxib 90 mg treatment sequence will receive etoricoxib 90 mg tablets administered orally once daily for 6 weeks in Part 1 and will not participate in Part 2 of the study. | Drug: Etoricoxib 90 mg<br>* One tablet orally once daily for 6 weeks.<br>* Other names: MK-0663;Drug: Placebo to Etoricoxib 90 mg<br>* One tablet orally once daily for 6 weeks<br>|
| Placebo Comparator: Placebo<br>The placebo treatment sequence will receive matching placebo to etoricoxib tablets administered orally once daily for 6 weeks in Part 1 and will not participate in Part 2 of the study. | Drug: Placebo to Etoricoxib 60 mg<br>* One tablet orally once daily for 6 weeks.<br>Drug: Placebo to Etoricoxib 90 mg<br>* One tablet orally once daily for 6 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 DAS28-CRP in Part 1 (Etoricoxib vs. Placebo) | Disease Activity Score Using C-Reactive Protein [DAS28-CRP] (0 - 10 Range). The DAS28-CRP index is a composite score of weighted components including tender joint counts of 28, swollen joint counts of 28, patient global assessment of disease activity, and C-reactive protein (CRP). For each observation (Baseline, Week 2, 4, 6, 10, 12), components were combined into a single DAS28-CRP score using the following algorithm: 0.56*square root (sqrt) (tender joint count [28])+0.28*sqrt(swollen joint count [28] )+0.36* ln(crp+1) + 0.014* Patient Global Assessment of Disease Activity + 0.96. The primary objectives of the study compared the efficacy of etoricoxib (90 mg, 60 mg) to placebo in Part 1 of this study so data for only these 3 arms are displayed. | Baseline and Week 6 | 
| Time-Weighted Average Change From Baseline in Patient Global Assessment of Pain in Part 1 (Etoricoxib vs. Placebo) | A participant overall assessment of pain on a visual analog scale (VAS) was assessed with a question concerning the amount of pain due to arthritis during the past 48 hours. Pain was assessed on an 100 mm VAS scale with a left-hand marker no pain (0 mm) or right-hand marker extreme pain (100 mm). The primary objectives of the study compared the efficacy of etoricoxib (90 mg, 60 mg) to placebo in Part 1 of this study so data for only these 3 arms are displayed. | Baseline and Week 6 | 
| Percentage of Participants Who Experienced at Least One Adverse Event (AE) | An AE is defined as any unfavorable and unintended sign including an abnormal laboratory finding, symptom or disease associated with the use of a medical treatment or procedure, regardless of whether it is considered related to the medical treatment or procedure. | Up to 112 days | 
| Percentage of Participants Who Discontinued Study Drug Due to an AE | An AE is defined as any unfavorable and unintended sign including an abnormal laboratory finding, symptom or disease associated with the use of a medical treatment or procedure, regardless of whether it is considered related to the medical treatment or procedure. | Up to Week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time-Weighted Average Change From Baseline in DAS28-CRP in Part 1 (Etoricoxib 90 mg vs. Etoricoxib 60 mg) | Disease Activity Score Using C-Reactive Protein [DAS28-CRP] (0 - 10 Range). The DAS28-CRP index is a composite score of weighted components including tender joint counts of 28, swollen joint counts of 28, patient global assessment of disease activity, and C-reactive protein (CRP). For each observation (Baseline, Week 2, 4, 6, 10, 12), components were combined into a single DAS28-CRP score using the following algorithm: 0.56*square root (sqrt) (tender joint count [28])+0.28*sqrt(swollen joint count [28] )+0.36* ln(crp+1) + 0.014* Patient Global Assessment of Disease Activity + 0.96. The key secondary objectives compared the relative efficacy between etoricoxib 90 mg and 60 mg in Part 1 of this study so data for only these 2 arms are displayed. | Baseline and Week 6 | 
| Time-Weighted Average Change From Baseline in Patient Global Assessment of Pain in Part 1 (Etoricoxib 90 mg vs. Etoricoxib 60 mg) | A participant overall assessment of pain on a visual analog scale (VAS) was assessed with a question concerning the amount of pain due to arthritis during the past 48 hours. Pain was assessed on an 100 mm VAS scale with a left-hand marker no pain (0 mm) or right-hand marker extreme pain (100 mm). The key secondary objectives compared the relative efficacy between etoricoxib 90 mg and 60 mg in Part 1 of this study so data for only these 2 arms are displayed. | Baseline and Week 6 | 
| Average Change From Week 6 in Patient Global Assessment of Pain Over Weeks 10 and 12 in Part 2 Among Pain Inadequate Responders From Part 1 | A participant overall assessment of pain on a visual analog scale (VAS) was assessed with a question concerning the amount of pain due to arthritis during the past 48 hours. Pain was assessed on an 100 mm VAS scale with a left-hand marker no pain (0 mm) or right-hand marker extreme pain (100 mm). In those participants who were considered inadequate responders to etoricoxib 60 mg in Part 1 (defined as a participant with <50% improvement from baseline in PGAP [VAS] at Week 6), the incremental benefit of increasing the etoricoxib dose from 60 mg (in Part 1) to 90 mg (in Part 2) compared to remaining on 60 mg in Part 2 was evaluated via average change from Week 6 over Weeks 10 and 12 in Patient Global Assessment of Pain score. Therefore, data for only these 2 arms are displayed. | Week 6 and Week 10 to Week 12 |