The Single Dose Pharmacokinetics of Two and Proof of Efficacy of One New Etoricoxib Gel Formulation in Participants With Osteoarthritis (MK-0663-168)

Study Overview
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Brief Summary
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Study Part 1 is designed to assess the plasma pharmacokinetics of etoricoxib (ETOR) 4% dimethyl sulfoxide (DMSO) and propylene glycol (PG) formulations, each at 2 different doses, upon single-dose topical administration on the knee of osteoarthritis participants. Study Part 2 is designed to evaluate the efficacy of topical etoricoxib vs. placebo in the treatment of osteoarthritis of the knee. The primary hypothesis is that topical etoricoxib will be more effective than placebo in the treatment of osteoarthritis of the knee over 2 weeks of treatment as assessed by time-weighted average change from baseline on the Western Ontario and McMaster Universities Arthritis Index (WOMAC) Visual Analogue (VA) 3.0 pain subscale.

Detailed Description
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Part I of the study will consist of a single-dose, open-label, randomized, four-way cross over study with topical administration of etoricoxib gel on the knee of osteoarthritis participants. The washout between successive dose administrations will be at least one week. Part 2 of the study will consist of double-blind, randomized, placebo-controlled, parallel groups, multiple dose, twice daily topical administration of etoricoxib or placebo gel on the knee of osteoarthritis participants for a period of two weeks.

Official Title
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A Study to Assess the Single Dose Pharmacokinetics of Two and Proof of Efficacy of One New Etoricoxib Gel Formulation in Osteoarthritis Patients

Conditions
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Osteoarthritis Pain

Intervention / Treatment
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* Drug: Etoricoxib 75 mg 4% DMSO Gel
* Drug: Etoricoxib 75 mg 4% PG Gel
* Drug: Etoricoxib 150 mg 4% DMSO Gel
* Drug: Etoricoxib 150 mg 4% PG Gel
* Drug: Etoricoxib 163 mg 4% DMSO gel
* Drug: Placebo
* Drug: Etoricoxib 50 mg 4% DMSO
* Drug: Matching Placebo to Etoricoxib 50 mg 4% DMSO Gel


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria Has diagnosis of osteoarthritis of the knee (tibio-femoral joint) for >6 months based on clinical and radiographic criteria; Has a diagnosis of American Rheumatology Association (ARA) functional Class I, II, or III; The knee designated as the study joint must be the participant's primary source of pain/disability in the lower extremity. If both knees are affected, the most painful joint will be selected for evaluation for inclusion and clinical response; Female participants of childbearing potential must demonstrate a serum beta human chorionic gonadotropin (β-hCG) level consistent with a non-gravid state at the screening visit and urine β-hCG at Day -1 prior to first dosing and agree to use adequate oral or barrier contraception or abstain from sexual contact at least 7 days prior to treatment and continuing through the treatment period or a discontinuation visit; Willing to limit alcohol intake (beer 8 ounces, wine 4 ounces, liquor 1 ounce) to no more than 14 drinks a week (no more than 2 in a day) and to avoid unaccustomed strenuous physical activity (e.g., unaccustomed weight lifting, initiation of physical therapy) for the duration of the study; Judged to be in general good health with the exception of osteoarthritis based on medical history, physical examination, and routine laboratory tests. For Part 2, if the participant is a regular user of non-steroidal anti-inflammatory drugs (NSAIDs) including coxibs he/she must report a history of positive therapeutic benefit in osteoarthritis of the knee with NSAID/coxibs in the past; For Part 2, participants must be taking a single NSAID on a regular basis and at a prescription strength for at least 30 days prior to study screening (regular basis is defined as at least 25 of the previous 30 days) for treatment of symptoms of osteoarthritis. Exclusion Criteria: Has a concurrent medical/arthritic disease; History of acute ligamentous or meniscal injury of the study joint within the previous 2 years or arthroscopy of the affected knee within 6 months prior to study entry; Is a candidate for imminent joint replacement; Has clinical or laboratory evidence of significant renal, gastrointestinal, pulmonary, hepatic, endocrine, neurological (apart from migraine), or other systemic disease that in the opinion of the investigator contraindicates the use of etoricoxib; Has congestive heart failure with symptoms that occur at rest or minimal activity; Has unstable angina that occurs at rest or with minimal activity; Has uncontrolled hypertension (sitting diastolic blood pressure >95 mm Hg, or sitting systolic blood pressure >165 mm Hg); Has a history of stroke or transient ischemic attack (TIA) within the previous 6 months; Has a history of hepatitis/hepatic disease that has been active within the previous 2 years; Has a history of neoplastic disease; Is currently a user (including recreational use) of any illicit drugs, or has a history of drug or alcohol abuse within the past 5 years; Is allergic of has hypersensitivity to aspirin, ibuprofen, rofecoxib, celecoxib, valdecoxib, other NSAIDs, acetaminophen, or sulfa drugs; Has used intravenous, intramuscular, or oral corticosteroids within 1 month of study entry; Has used glucosamine and/or chondroitin sulfate for <6 months prior to study start; Has used intra-articular steroids, HYALGAN™ (sodium hyaluronate, Sanofi Pharmaceuticals), or SYNVISC™ (hylan G-F 20, Wyeth-Ayerst Pharmaceuticals) to the study joint within 3 months of entry into the study or intra-articular steroids, HYALGAN™, or SYNVISC™ to any other joint within 1 month of study entry; Has used topical, oral or systemic analgesic medications within 2 weeks of study entry and for the duration of the study; Requires treatment with warfarin, heparin, high-dose aspirin (>325 mg), or digoxin; Has used Arcoxia® within 2 weeks of study entry.

Ages Eligible for Study
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Minimum Age: 40 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: Crossover Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Pt 1: ETOR 75 DMSO/ETOR 150 PG/ETOR 75 PG/ETOR 150 DMSO<br>Single-dose etoricoxib 75 mg (1.97 mL) 4% DMSO gel, followed by single-dose etoricoxib 150 mg (4.30 mL) 4% PG gel, followed by single-dose etoricoxib 75 mg (2.15 mL) 4% PG gel, followed by single-dose etoricoxib 150 mg (3.94 mL) 4% DMSO gel. All treatments were applied topically. | Drug: Etoricoxib 75 mg 4% DMSO Gel<br>* Etoricoxib 75 mg 4% DMSO gel applied topically.<br>Drug: Etoricoxib 75 mg 4% PG Gel<br>* Etoricoxib 75 4% PG gel applied topically.<br>Drug: Etoricoxib 150 mg 4% DMSO Gel<br>* Etoricoxib 150 mg 4% DMSO gel applied topically.<br>Drug: Etoricoxib 150 mg 4% PG Gel<br>* Etoricoxib 150 mg 4% PG gel applied topically.<br>|
| Experimental: Pt 1: ETOR 75 PG/ETOR 75 DMSO/ETOR 150 DMSO/ETOR 150 PG<br>Single-dose etoricoxib 75 mg (2.15 mL) 4% PG gel, followed by single-dose etoricoxib 75 mg (1.97 mL) 4% DMSO gel, followed by single-dose etoricoxib 150 mg (3.94 mL) 4% DMSO gel, followed by single-dose etoricoxib 150 mg (4.30 mL) 4% PG gel. All treatments were applied topically. | Drug: Etoricoxib 75 mg 4% DMSO Gel<br>* Etoricoxib 75 mg 4% DMSO gel applied topically.<br>Drug: Etoricoxib 75 mg 4% PG Gel<br>* Etoricoxib 75 4% PG gel applied topically.<br>Drug: Etoricoxib 150 mg 4% DMSO Gel<br>* Etoricoxib 150 mg 4% DMSO gel applied topically.<br>Drug: Etoricoxib 150 mg 4% PG Gel<br>* Etoricoxib 150 mg 4% PG gel applied topically.<br>|
| Experimental: Pt 1: ETOR 150 DMSO/ETOR 75 PG/ETOR 150 PG/ETOR 75 DMSO<br>Single-dose etoricoxib 150 mg (3.94 mL) 4% DMSO gel, followed by single-dose etoricoxib 75 mg (2.15 mL) 4% PG gel, followed by single-dose etoricoxib 150 mg (4.30 mL) 4% PG gel, followed by single-dose etoricoxib 75 mg (1.97 mL) 4% DMSO gel. All treatments were applied topically. | Drug: Etoricoxib 75 mg 4% DMSO Gel<br>* Etoricoxib 75 mg 4% DMSO gel applied topically.<br>Drug: Etoricoxib 75 mg 4% PG Gel<br>* Etoricoxib 75 4% PG gel applied topically.<br>Drug: Etoricoxib 150 mg 4% DMSO Gel<br>* Etoricoxib 150 mg 4% DMSO gel applied topically.<br>Drug: Etoricoxib 150 mg 4% PG Gel<br>* Etoricoxib 150 mg 4% PG gel applied topically.<br>|
| Experimental: Pt 1: ETOR 150 PG/ETOR 150 DMSO/ETOR 75 PG/ETOR 75 DMSO<br>Single-dose etoricoxib 150 mg (4.30 mL) 4% PG gel, followed by single-dose etoricoxib 150 mg (3.94 mL) 4% DMSO gel, followed by single-dose etoricoxib 75 mg (1.97 mL) 4% DMSO gel, followed by single-dose etoricoxib 75 mg (2.15 mL) 4% PG gel. All treatments were applied topically. | Drug: Etoricoxib 75 mg 4% DMSO Gel<br>* Etoricoxib 75 mg 4% DMSO gel applied topically.<br>Drug: Etoricoxib 75 mg 4% PG Gel<br>* Etoricoxib 75 4% PG gel applied topically.<br>Drug: Etoricoxib 150 mg 4% DMSO Gel<br>* Etoricoxib 150 mg 4% DMSO gel applied topically.<br>Drug: Etoricoxib 150 mg 4% PG Gel<br>* Etoricoxib 150 mg 4% PG gel applied topically.<br>|
| Experimental: Pt 1: ETOR OD/ ETOR 150 DMSO/ ETOR 75 DMSO/ ETOR 75 PG<br>Single-dose etoricoxib 163 mg (4.30 mL) 4% DMSO gel (DMSO formulation administered in error/overdose [OD]), followed by single-dose etoricoxib 150 mg (3.94 mL) 4% DMSO gel, followed by single-dose etoricoxib 75 mg (1.97 mL) 4% DMSO gel, followed by single-dose etoricoxib 75 mg (2.15 mL) 4% PG gel. All treatments were applied topically. | Drug: Etoricoxib 75 mg 4% DMSO Gel<br>* Etoricoxib 75 mg 4% DMSO gel applied topically.<br>Drug: Etoricoxib 75 mg 4% PG Gel<br>* Etoricoxib 75 4% PG gel applied topically.<br>Drug: Etoricoxib 150 mg 4% DMSO Gel<br>* Etoricoxib 150 mg 4% DMSO gel applied topically.<br>Drug: Etoricoxib 163 mg 4% DMSO gel<br>* Etoricoxib 163 mg 4% DMSO gel applied topically<br>|
| Other: Pt 1: Placebo (Deviation)<br>Participants randomized to a treatment sequence in Part 1 who received single dose placebo gel (1.97 or 3.94 mL) applied topically in error instead of active study drug and dropped out after the first treatment period in the sequence. Included in the safety assessments only. | Drug: Placebo<br>* Placebo gel applied topically.<br>|
| Experimental: Pt 2: ETOR 50 DMSO<br>Etoricoxib 50 mg (1.31 mL, 4% DMSO gel) applied topically twice daily to the affected knee for a period of 2 weeks. | Drug: Etoricoxib 50 mg 4% DMSO<br>* Etoricoxib 50 mg 4% DMSO gel applied topically.<br>|
| Placebo Comparator: Pt 2: Placebo<br>Matching placebo to etoricoxib 50 mg 1.31 mL 4% DMSO gel applied topically twice daily to the affected knee for a period of 2 weeks. | Drug: Matching Placebo to Etoricoxib 50 mg 4% DMSO Gel<br>* Matching Placebo to Etoricoxib 50 mg 4% DMSO gel applied topically.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Study Part 1: Maximum Concentration (Cmax) of ETOR After Single Dosing | Cmax determined for the period up to 72 hours post-single application. Descriptive statistics are expressed as the geometric least squares mean (GLSM). Cmax with value 0 included in calculation of GLSMs with a value of 0.5*LLOQ (=0.5 h*ng/ml). | Predose and 0.5, 1, 2, 3, 4, 5, 6, 7, 9, 12, 16, 24, 36, 48, and 72 hours post-application | 
| Study Part 1: Time to Maximum Concentration (Tmax) of ETOR After Single Dosing | Tmax determined for the period up to 72 hours post-single application. | Predose and 0.5, 1, 2, 3, 4, 5, 6, 7, 9, 12, 16, 24, 36, 48, and 72 hours post-application | 
| Study Part 1: Area Under the Concentration-time Curve of ETOR From Time 0 to Last (AUC0-last) After Single Dosing | Area under the observed concentration-time curve from time zero to the last quantifiable time point determined for the period up to 72 hours post-single application. The area was calculated according to the linear up/log down trapezoidal rule. AUC0-last is an estimate of total plasma exposure. Descriptive statistics are expressed as the GLSM. AUC with value 0 included in calculation of GLSMs with a value of 0.5*LLOQ (=0.5 h*ng/ml). | Predose and 0.5, 1, 2, 3, 4, 5, 6, 7, 9, 12, 16, 24, 36, 48, and 72 hours post-application | 
| Study Part 2: Change From Baseline in Mean Participant Score on the Western Ontario and McMaster Universities Arthritis Index (WOMAC) Visual Analog (VA) 3.1 Pain Scale | The WOMAC VA 3.1 Pain subscale is a self-administered questionnaire assessing lower extremity pain due to osteoarthritis that was completed by participants 2 to 3 hours post morning dose. The WOMAC Pain Subscale had five questions with answers to each item assessed on a 100 mm VA scale (0 = no pain; 100 = extreme pain). The score for each item was summed and the overall score ranged from 0 to 500 (increasing severity). The time weighted average up to day x was calculated as the sum of rectangles under the curve for successive intervals prior to day x as defined by timepoints at which assessments were made. The time weighted change from baseline was calculated. A negative mean change from baseline indicates improvement in pain. | Baseline (Day -1), Day 2, Day 4, Day 7, Day 11, Day 14 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Study Part 2: Change From Baseline in Mean Participant Score on the WOMAC VA 3.1 Stiffness Scale | The WOMAC VA 3.1 Stiffness subscale is a self-administered questionnaire assessing lower extremity stiffness due to osteoarthritis that was completed by participants 2 to 3 hours post morning dose. The WOMAC Stiffness subscale had two questions with answers to each item assessed on a 100 mm VA scale (0 = no stiffness; 100 = extreme stiffness). The score for each item was summed and the overall score ranged from 0 to 200 (increasing severity). The time weighted average up to day x was calculated as the sum of rectangles under the curve for successive intervals prior to day x as defined by timepoints at which assessments were made. The time weighted change from baseline was calculated. A negative mean change from baseline indicates improvement in stiffness. | Baseline (Day -1), Day 2, Day 4, Day 7, Day 11, Day 14 | 
| Study Part 2: Change From Baseline in Mean Participant Score on the WOMAC VA 3.1 Physical Functioning Scale | The WOMAC VA 3.1 Physical Functioning subscale is a self-administered questionnaire assessing lower extremity physical function due to osteoarthritis that was completed by participants 2 to 3 hours post morning dose. The WOMAC Physical Functioning subscale had 17 questions with answers to each item assessed on a 100 mm VA scale (0 = no difficulty; 100 = extreme difficulty). The score for each item was summed and the overall score ranged from 0 to 1700 (increasing severity). The time weighted average up to day x was calculated as the sum of rectangles under the curve for successive intervals prior to day x as defined by timepoints at which assessments were made. The time weighted change from baseline was calculated. A negative mean change from baseline indicates improvement in physical function. | Baseline (Day -1), Day 2, Day 4, Day 7, Day 11, Day 14 | 
| Study Part 2: Percentage of Participants by Category on Patient Global Assessment of Response to Therapy (PGART) | The PGART is a self-administered questionnaire completed by participants. Participant assessment of response of arthritis to study medication was assessed on a 5-point Likert scale ('very well', 'well', 'fair', 'poor', and 'very poor'). | Day 2, Day 4, Day 7, Day 11, Day 14, post-trial (up to Day 28) | 
| Study Parts 1 and 2: Number of Participants Who Experienced at Least One Adverse Event | An adverse event 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. | Study Part 1: up to Day 47; Study Part 2: up to Day 28 | 
| Study Parts 1 and 2: Number of Participants Who Discontinued Study Drug Due to an Adverse Event | An adverse event 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. | Study Part 1: up to Day 47; Study Part 2: up to Day 28 |