A Study Of The Safety And Efficacy Of PF-04191834 In Patients With Osteoarthritis Of The Knee

Study Overview
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Brief Summary
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PF-04191834 works in animal models by inhibiting one of the enzymes, 5-lipoxygenasein which is involved in the pathway that causes inflammation and pain. The purpose of this study is to test how effective, safe and tolerated PF-04191834 is in patients with osteoarthritis of the knee by itself or with naproxen, particularly to test if patients have less pain.

Detailed Description
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This study has been terminated in response to a reported serious adverse event (SAE). The sponsor's assessment of the limited data available at the time of the initial SAE report was that the SAE may alter the potential benefit - risk profile of the study medication.

Official Title
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A Phase 2 Randomized, Double-Blinded, Double-Dummy, Placebo And Active Controlled Two Cohort Two-Way Cross-Over, Multi-Centre Clinical Trial To Examine The Pain Relief Produced By 2 Weeks Of Daily Oral Administration Of A 5-Lipoxygenase (5-Lox) Inhibitor PF-04191834 Alone And In Combination With Naproxen In Patients With Flare-Enriched Osteoarthritis Of The Knee

Conditions
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Osteoarthritis, Knee

Intervention / Treatment
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* Drug: PF-04191834
* Drug: PF-04191834 placebo
* Drug: Naproxen placebo
* Drug: PF-04191834 placebo
* Drug: PF-04191834
* Drug: Naproxen placebo
* Drug: PF-04191834
* Drug: Naproxen
* Drug: PF-04191834 placebo
* Drug: Naproxen
* Drug: PF-04191834 placebo
* Drug: PF-04191834


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subjects must have a diagnosis of osteoarthritis based on the American College of Rheumatology criteria confirmed by an X-ray Subjects must be willing and able to stop all current pain therapy for the duration of the study Subjects must be willing and able to complete a daily diary Exclusion Criteria: BMI of >39 kg/m2 Known allergy or hypersensitivity to naproxen Any condition or medical history that might interfere with the subject's ability to complete the study visits and assessments

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 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: PF-04191834 followed by placebo<br>PF-04191834 600 mg BID dose followed by matched placebo plus naproxen placebo. | Drug: PF-04191834<br>* 100 mg tablets of PF-04191834 to provide a 600 mg BID dose administered for two weeks<br>Drug: PF-04191834 placebo<br>* Matching PF-04191834 placebo tablets to be administered BID for two weeks<br>Drug: Naproxen placebo<br>* Matching naproxen placebo tablets to be administered BID for 4 weeks<br>|
| Experimental: Placebo followed by PF-04191834<br>Placebo followed by 600 mg BID dose of PF-04191834 plus naproxen placebo. | Drug: PF-04191834 placebo<br>* Matching PF-04191834 placebo tablets to be administered BID for two weeks<br>Drug: PF-04191834<br>* 100 mg tablets of PF-04191834 to provide a 600 mg BID dose administered for two weeks<br>Drug: Naproxen placebo<br>* Matching naproxen placebo tablets to be administered BID for 4 weeks<br>|
| Experimental: PF-04191834+Naproxen followed by Naproxen<br>PF-04191834 600 mg BID + Naproxen 500 mg BID followed by Naproxen 500 mg BID plus PF-04191834 placebo | Drug: PF-04191834<br>* 100 mg tablets of PF-04191834 to provide a 600 mg BID dose administered for two weeks<br>Drug: Naproxen<br>* Naproxen 500 mg tablet administered BID for a total of four weeks<br>Drug: PF-04191834 placebo<br>* Matching PF-04191834 placebo tablets to be administered BID for two weeks<br>|
| Experimental: Naproxen followed by PF-04191834+Naproxen<br>Naproxen 500 mg BID followed by PF-04191834 600 mg BID + Naproxen 500 mg BID | Drug: Naproxen<br>* Naproxen 500 mg tablet administered BID for a total of four weeks<br>Drug: PF-04191834 placebo<br>* Matching PF-04191834 placebo tablets to be administered BID for two weeks<br>Drug: PF-04191834<br>* 100 mg tablets of PF-04191834 to provide a 600 mg BID dose administered for two weeks<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Western Ontario & McMaster (WOMAC) Osteoarthritis Index Pain Score at the End of Treatment Period 1 | The WOMAC Pain subscale, comprised of 5 questions regarding the amount of pain experienced in the index joint, was calculated as the mean of the scores from the 5 individual questions. The WOMAC Pain subscale scores for each question range from 0 to 4 giving a possible overall score range of 0-20, with higher scores indicating higher pain. | Baseline (Day 1 of Visit 3) and end of treatment Period 1 (Day 15+1 of Visit 5) | 
| Change From Baseline in Western Ontario & McMaster (WOMAC) Osteoarthritis Index Pain Score at the End of Treatment Period 2 | The WOMAC Pain subscale, comprised of 5 questions regarding the amount of pain experienced in the index joint, was calculated as the mean of the scores from the 5 individual questions. The WOMAC Pain subscale scores for each question range from 0 to 4 giving a possible overall score range of 0-20, with higher scores indicating higher pain. | Baseline (Day 28 of Visit 7) and end of treatment Period 2 (Day 43+1 of Visit 9) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| WOMAC Stiffness Domain Score | The WOMAC Stiffness subscale, comprised of 2 questions regarding the amount of stiffness experienced in the index joint, was calculated as the mean of the scores from the 2 individual questions. The WOMAC Stiffness subscale scores for each question range from 0 to 4 giving a possible overall score range of 0-8, with higher scores indicating more stiffness. | Baseline (Day 1 of Visit 3 for Period 1 and Day 28 of Visit 7 for Period 2), Day 15+1 of Visit 5 for Period 1, and Day 43+1 of Visit 9 for Period 2 | 
| WOMAC Physical Function Domain Score | The WOMAC Physical Function subscale refers to the participant's ability to move around and perform usual activities of daily living. The WOMAC Physical Function subscale, comprised of 17 questions regarding the degree of difficulty experienced in the index joint, was calculated as the mean of the scores from the 17 individual questions. The WOMAC Physical Function subscale scores for each question range from 0 to 4 giving a possible overall score range of 0-68, with higher scores indicating worse function. | Baseline (Day 1 of Visit 3 for Period 1 and Day 28 of Visit 7 for Period 2), Day 15+1 of Visit 5 for Period 1, and Day 43+1 of Visit 9 for Period 2 | 
| WOMAC Total Score | The WOMAC total score was calculated as the sum of Pain subscale score (5 questions), Stiffness subscale score (2 questions) and Physical Function subscale score (17 questions), with a total of 24 questions(score range:0=none, 4=extreme) giving a possible total score range from 0 to 96 . lower subscale scores represent less pain, less stiffness, or better physical performance. | Baseline (Day 1 of Visit 3 for Period 1 and Day 28 of Visit 7 for Period 2), Day 15+1 of Visit 5 for Period 1, and Day 43+1 of Visit 9 for Period 2 | 
| Importance Weighted Total WOMAC Score | Importance weighted total WOMAC score was calculated using all subscales including Pain, Stiffness and Physical Function subscales (24 questions in total,score range: 0=none to 4= extreme,giving a possible overall score range of 0-96).Lower subscale scores represent less pain, less stiffness, or better physical performance. | Baseline (Day 1 of Visit 3 for Period 1 and Day 28 of Visit 7 for Period 2), Day 15+1 of Visit 5 for Period 1, and Day 43+1 of Visit 9 for Period 2 | 
| Daily Diary Pain Score During Week 1 of Each Treatment Period | The daily diary pain was assessed using an 11-point numerical rating scale (NRS) ranging from 0 to 10 (0 = no pain; 10 = the worst pain possible). | 4 days prior to baseline visits (Visits 3 for Period 1 and Vist 8 for Period 2) up to 7 days after baseline visits | 
| Daily Diary Pain Score During Week 2 of Each Treatment Period | The daily diary pain was assessed using an 11-point numerical rating scale (NRS) ranging from 0 to 10 (0 = no pain; 10 = the worst pain possible). | Over the last 4 days before baseline visits (Visits 3 for Period 1 and Visit 8 for Period 2) and over the last 6 days before Visit 5 for Period 1 and Visit 9 for Period 2 | 
| Rescue Medication Use | Rescue medication use was collected daily in a daily diary, in which participants noted the amount of rescue medication (number of pills) taken each day. Participants were provided with rescue medication paracetamol/acetaminophen throughout the study including the Washout Period and the Initial Pain Assessment Period. Paracetamol/acetaminophen was taken as needed to a maximum of 2000 mg per day, but must be discontinued 48 hours prior to the Baseline visit (Visit 3). From Visit 3 onwards, participants might take up to 2000 mg of paracetamol/acetaminophen per day up to 3 days per week. | Day -7 (Visit 2) up to 28-day follow-up (Visit 10) | 
| Plasma Concentration of PF-04191834 |  | Pre-dose and post-dose (1 to 3 hours) on Days 1, 8, 15, 29, 36, and 43 | 
| Urinary Leukotriene E4 (LTE4) Levels | LTE4 is a terminal metabolic product of arachidonic acid by 5-LO. Its synthesis is dependent upon the activity of 5-LO and it is eliminated through urinary clearance. Hence, the level of urinary LTE4 (uLTE4) excretion may be an indicator of endogenous 5-LO activity. | Day -7 (Visit 2) up to Day 43 (Visit 9 or End of Treatment Period 2) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Cross-over, safety, efficacy, tolerability, osteoarthritis, knee, pain