Osteoarthritis, Knee
Conditions
Keywords
Cross-over, safety, efficacy, tolerability, osteoarthritis, knee, pain
Brief summary
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
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.
Interventions
DRUGPF-04191834 placebo
Matching PF-04191834 placebo tablets to be administered BID for two weeks
DRUGNaproxen placebo
Matching naproxen placebo tablets to be administered BID for 4 weeks
DRUGNaproxen
Naproxen 500 mg tablet administered BID for a total of four weeks
DRUGPF-04191834
100 mg tablets of PF-04191834 to provide a 600 mg BID dose administered for two weeks
Sponsors
Pfizer
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Western Ontario & McMaster (WOMAC) Osteoarthritis Index Pain Score at the End of Treatment Period 1 | Baseline (Day 1 of Visit 3) and end of treatment Period 1 (Day 15+1 of Visit 5) | 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. |
| Change From Baseline in Western Ontario & McMaster (WOMAC) Osteoarthritis Index Pain Score at the End of Treatment Period 2 | Baseline (Day 28 of Visit 7) and end of treatment Period 2 (Day 43+1 of Visit 9) | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| WOMAC Total Score | 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 | 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. |
| Importance Weighted Total WOMAC Score | 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 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. |
| Daily Diary Pain Score During Week 1 of Each Treatment Period | 4 days prior to baseline visits (Visits 3 for Period 1 and Vist 8 for Period 2) up to 7 days after baseline visits | 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). |
| WOMAC Stiffness Domain Score | 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 | 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. |
| Rescue Medication Use | Day -7 (Visit 2) up to 28-day follow-up (Visit 10) | 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. |
| 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 | Day -7 (Visit 2) up to Day 43 (Visit 9 or End of Treatment Period 2) | 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. |
| Daily Diary Pain Score During Week 2 of Each Treatment Period | 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 | 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). |
| WOMAC Physical Function Domain Score | 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 | 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. |
Countries
Canada, Sweden, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Entire Study Population Includes groups randomized to receive PF-04191834 first, placebo first, PF-04191834 plus naproxen first, and naproxen first. | 190 |
| Total | 190 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| First Intervention | Adverse Event | 0 | 3 | 2 | 3 |
| First Intervention | Other | 1 | 2 | 0 | 0 |
| First Intervention | Protocol Violation | 2 | 3 | 2 | 3 |
| First Intervention | Study terminated by sponsor | 8 | 8 | 7 | 8 |
| First Intervention | Withdrawal by Subject | 3 | 0 | 1 | 0 |
| Second Intervention | Adverse Event | 2 | 0 | 1 | 1 |
| Second Intervention | Other | 0 | 0 | 1 | 0 |
| Second Intervention | Protocol Violation | 0 | 1 | 1 | 0 |
| Second Intervention | Study terminated by sponsor | 7 | 5 | 5 | 3 |
| Second Intervention | Withdrawal by Subject | 0 | 1 | 0 | 0 |
Baseline characteristics
| Characteristic | Entire Study Population |
|---|---|
| Age Continuous | 59.4 Years STANDARD_DEVIATION 8.7 |
| Sex: Female, Male Female | 110 Participants |
| Sex: Female, Male Male | 80 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 35 / 79 | 43 / 81 | 39 / 81 | 42 / 83 |
| serious Total, serious adverse events | 0 / 79 | 1 / 81 | 2 / 81 | 0 / 83 |
Outcome results
Primary
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.
Time frame: Baseline (Day 1 of Visit 3) and end of treatment Period 1 (Day 15+1 of Visit 5)
Population: Full Analysis Set (FAS): included all participants randomized who received at least one dose of study drug, regardless of whether they had efficacy data.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| PF-04191834 Followed by Placebo | Change From Baseline in Western Ontario & McMaster (WOMAC) Osteoarthritis Index Pain Score at the End of Treatment Period 1 | Baseline | 11.3 Units on a scale | Standard Deviation 2.34 |
| PF-04191834 Followed by Placebo | Change From Baseline in Western Ontario & McMaster (WOMAC) Osteoarthritis Index Pain Score at the End of Treatment Period 1 | Change from Baseline | -1.2 Units on a scale | Standard Deviation 2.49 |
| Placebo Followed by PF-04191834 | Change From Baseline in Western Ontario & McMaster (WOMAC) Osteoarthritis Index Pain Score at the End of Treatment Period 1 | Change from Baseline | -1.6 Units on a scale | Standard Deviation 3.1 |
| Placebo Followed by PF-04191834 | Change From Baseline in Western Ontario & McMaster (WOMAC) Osteoarthritis Index Pain Score at the End of Treatment Period 1 | Baseline | 11.5 Units on a scale | Standard Deviation 2.81 |
| PF-04191834 + Naproxen Followed by Naproxen | Change From Baseline in Western Ontario & McMaster (WOMAC) Osteoarthritis Index Pain Score at the End of Treatment Period 1 | Baseline | 10.8 Units on a scale | Standard Deviation 2.6 |
| PF-04191834 + Naproxen Followed by Naproxen | Change From Baseline in Western Ontario & McMaster (WOMAC) Osteoarthritis Index Pain Score at the End of Treatment Period 1 | Change from Baseline | -1.9 Units on a scale | Standard Deviation 2.97 |
| Naproxen Followed by PF-04191834 + Naproxen | Change From Baseline in Western Ontario & McMaster (WOMAC) Osteoarthritis Index Pain Score at the End of Treatment Period 1 | Baseline | 11.1 Units on a scale | Standard Deviation 2.93 |
| Naproxen Followed by PF-04191834 + Naproxen | Change From Baseline in Western Ontario & McMaster (WOMAC) Osteoarthritis Index Pain Score at the End of Treatment Period 1 | Change from Baseline | -1.6 Units on a scale | Standard Deviation 2.93 |
Comparison: The analysis was a mixed model with random participant effect, period and treatment as fixed effects, utilizing the baseline scores (one for each treatment period) as inter- and intra- participant covariates.p-value: 0.06780% CI: [0.08, 1.04]ANCOVA
Comparison: The analysis was a mixed model with random participant effect, period and treatment as fixed effects, utilizing the baseline scores (one for each treatment period) as inter- and intra- participant covariates.p-value: 0.70180% CI: [-0.67, 0.28]ANCOVA
Primary
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.
Time frame: Baseline (Day 28 of Visit 7) and end of treatment Period 2 (Day 43+1 of Visit 9)
Population: Full Analysis Set (FAS): included all participants randomized who received at least one dose of study drug, regardless of whether they had efficacy data.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| PF-04191834 Followed by Placebo | Change From Baseline in Western Ontario & McMaster (WOMAC) Osteoarthritis Index Pain Score at the End of Treatment Period 2 | Baseline | 9.7 Units on a scale | Standard Deviation 3.53 |
| PF-04191834 Followed by Placebo | Change From Baseline in Western Ontario & McMaster (WOMAC) Osteoarthritis Index Pain Score at the End of Treatment Period 2 | Change from Baseline | -1.8 Units on a scale | Standard Deviation 2.58 |
| Placebo Followed by PF-04191834 | Change From Baseline in Western Ontario & McMaster (WOMAC) Osteoarthritis Index Pain Score at the End of Treatment Period 2 | Change from Baseline | -0.6 Units on a scale | Standard Deviation 2.44 |
| Placebo Followed by PF-04191834 | Change From Baseline in Western Ontario & McMaster (WOMAC) Osteoarthritis Index Pain Score at the End of Treatment Period 2 | Baseline | 8.6 Units on a scale | Standard Deviation 3.15 |
| PF-04191834 + Naproxen Followed by Naproxen | Change From Baseline in Western Ontario & McMaster (WOMAC) Osteoarthritis Index Pain Score at the End of Treatment Period 2 | Baseline | 9.7 Units on a scale | Standard Deviation 2.74 |
| PF-04191834 + Naproxen Followed by Naproxen | Change From Baseline in Western Ontario & McMaster (WOMAC) Osteoarthritis Index Pain Score at the End of Treatment Period 2 | Change from Baseline | -1.5 Units on a scale | Standard Deviation 3.64 |
| Naproxen Followed by PF-04191834 + Naproxen | Change From Baseline in Western Ontario & McMaster (WOMAC) Osteoarthritis Index Pain Score at the End of Treatment Period 2 | Baseline | 10.2 Units on a scale | Standard Deviation 3.47 |
| Naproxen Followed by PF-04191834 + Naproxen | Change From Baseline in Western Ontario & McMaster (WOMAC) Osteoarthritis Index Pain Score at the End of Treatment Period 2 | Change from Baseline | -2.1 Units on a scale | Standard Deviation 3.03 |
Comparison: The analysis was a mixed model with random participant effect, period and treatment as fixed effects, utilizing the baseline scores (one for each treatment period) as inter- and intra- participant covariates.p-value: 0.06780% CI: [0.08, 1.04]ANCOVA
Comparison: The analysis was a mixed model with random participant effect, period and treatment as fixed effects, utilizing the baseline scores (one for each treatment period) as inter- and intra- participant covariates.p-value: 0.70180% CI: [-0.67, 0.28]ANCOVA
Secondary
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).
Time frame: 4 days prior to baseline visits (Visits 3 for Period 1 and Vist 8 for Period 2) up to 7 days after baseline visits
Population: Full Analysis Set (FAS): included all participants randomized who received at least one dose of study drug, regardless of whether they had efficacy data.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| PF-04191834 Followed by Placebo | Daily Diary Pain Score During Week 1 of Each Treatment Period | Baseline of Period 1 | 6.5 Units on a scale | Standard Deviation 1.56 |
| PF-04191834 Followed by Placebo | Daily Diary Pain Score During Week 1 of Each Treatment Period | Week 1 of Period 1 | 6.2 Units on a scale | Standard Deviation 1.71 |
| PF-04191834 Followed by Placebo | Daily Diary Pain Score During Week 1 of Each Treatment Period | Baseline of Period 2 | 5.1 Units on a scale | Standard Deviation 2.18 |
| PF-04191834 Followed by Placebo | Daily Diary Pain Score During Week 1 of Each Treatment Period | Week 1 of Period 2 | 5.1 Units on a scale | Standard Deviation 2.27 |
| Placebo Followed by PF-04191834 | Daily Diary Pain Score During Week 1 of Each Treatment Period | Week 1 of Period 1 | 6.5 Units on a scale | Standard Deviation 1.52 |
| Placebo Followed by PF-04191834 | Daily Diary Pain Score During Week 1 of Each Treatment Period | Baseline of Period 2 | 4.8 Units on a scale | Standard Deviation 2.31 |
| Placebo Followed by PF-04191834 | Daily Diary Pain Score During Week 1 of Each Treatment Period | Week 1 of Period 2 | 4.8 Units on a scale | Standard Deviation 2.48 |
| Placebo Followed by PF-04191834 | Daily Diary Pain Score During Week 1 of Each Treatment Period | Baseline of Period 1 | 6.9 Units on a scale | Standard Deviation 1.36 |
| PF-04191834 + Naproxen Followed by Naproxen | Daily Diary Pain Score During Week 1 of Each Treatment Period | Baseline of Period 2 | 5.4 Units on a scale | Standard Deviation 1.69 |
| PF-04191834 + Naproxen Followed by Naproxen | Daily Diary Pain Score During Week 1 of Each Treatment Period | Week 1 of Period 1 | 5.4 Units on a scale | Standard Deviation 1.8 |
| PF-04191834 + Naproxen Followed by Naproxen | Daily Diary Pain Score During Week 1 of Each Treatment Period | Week 1 of Period 2 | 4.7 Units on a scale | Standard Deviation 1.87 |
| PF-04191834 + Naproxen Followed by Naproxen | Daily Diary Pain Score During Week 1 of Each Treatment Period | Baseline of Period 1 | 6.4 Units on a scale | Standard Deviation 1.45 |
| Naproxen Followed by PF-04191834 + Naproxen | Daily Diary Pain Score During Week 1 of Each Treatment Period | Week 1 of Period 2 | 5.0 Units on a scale | Standard Deviation 2.04 |
| Naproxen Followed by PF-04191834 + Naproxen | Daily Diary Pain Score During Week 1 of Each Treatment Period | Week 1 of Period 1 | 5.6 Units on a scale | Standard Deviation 2.05 |
| Naproxen Followed by PF-04191834 + Naproxen | Daily Diary Pain Score During Week 1 of Each Treatment Period | Baseline of Period 1 | 6.7 Units on a scale | Standard Deviation 1.55 |
| Naproxen Followed by PF-04191834 + Naproxen | Daily Diary Pain Score During Week 1 of Each Treatment Period | Baseline of Period 2 | 5.6 Units on a scale | Standard Deviation 1.85 |
Comparison: The analysis was a mixed model with random participant effect, period and treatment as fixed effects, utilizing the baseline scores (one for each treatment period) as inter- and intra- participant covariates.80% CI: [-0.18, 0.2]ANCOVA
Comparison: The analysis was a mixed model with random participant effect, period and treatment as fixed effects, utilizing the baseline scores (one for each treatment period) as inter- and intra- participant covariates.80% CI: [-0.07, 0.31]ANCOVA
Secondary
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).
Time frame: 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
Population: Full Analysis Set (FAS): included all participants randomized who received at least one dose of study drug, regardless of whether they had efficacy data.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| PF-04191834 Followed by Placebo | Daily Diary Pain Score During Week 2 of Each Treatment Period | Baseline of Period 1 | 6.5 Units on a scale | Standard Deviation 1.56 |
| PF-04191834 Followed by Placebo | Daily Diary Pain Score During Week 2 of Each Treatment Period | Week 2 of Period 1 | 5.8 Units on a scale | Standard Deviation 1.91 |
| PF-04191834 Followed by Placebo | Daily Diary Pain Score During Week 2 of Each Treatment Period | Baseline of Period 2 | 5.1 Units on a scale | Standard Deviation 2.18 |
| PF-04191834 Followed by Placebo | Daily Diary Pain Score During Week 2 of Each Treatment Period | Week 2 of Period 2 | 4.8 Units on a scale | Standard Deviation 2.44 |
| Placebo Followed by PF-04191834 | Daily Diary Pain Score During Week 2 of Each Treatment Period | Week 2 of Period 1 | 5.8 Units on a scale | Standard Deviation 1.72 |
| Placebo Followed by PF-04191834 | Daily Diary Pain Score During Week 2 of Each Treatment Period | Baseline of Period 2 | 4.8 Units on a scale | Standard Deviation 2.31 |
| Placebo Followed by PF-04191834 | Daily Diary Pain Score During Week 2 of Each Treatment Period | Week 2 of Period 2 | 4.5 Units on a scale | Standard Deviation 2.58 |
| Placebo Followed by PF-04191834 | Daily Diary Pain Score During Week 2 of Each Treatment Period | Baseline of Period 1 | 6.9 Units on a scale | Standard Deviation 1.36 |
| PF-04191834 + Naproxen Followed by Naproxen | Daily Diary Pain Score During Week 2 of Each Treatment Period | Baseline of Period 2 | 5.4 Units on a scale | Standard Deviation 1.69 |
| PF-04191834 + Naproxen Followed by Naproxen | Daily Diary Pain Score During Week 2 of Each Treatment Period | Week 2 of Period 1 | 5.3 Units on a scale | Standard Deviation 1.66 |
| PF-04191834 + Naproxen Followed by Naproxen | Daily Diary Pain Score During Week 2 of Each Treatment Period | Week 2 of Period 2 | 4.4 Units on a scale | Standard Deviation 1.68 |
| PF-04191834 + Naproxen Followed by Naproxen | Daily Diary Pain Score During Week 2 of Each Treatment Period | Baseline of Period 1 | 6.4 Units on a scale | Standard Deviation 1.45 |
| Naproxen Followed by PF-04191834 + Naproxen | Daily Diary Pain Score During Week 2 of Each Treatment Period | Week 2 of Period 2 | 4.8 Units on a scale | Standard Deviation 2.18 |
| Naproxen Followed by PF-04191834 + Naproxen | Daily Diary Pain Score During Week 2 of Each Treatment Period | Week 2 of Period 1 | 5.6 Units on a scale | Standard Deviation 2.16 |
| Naproxen Followed by PF-04191834 + Naproxen | Daily Diary Pain Score During Week 2 of Each Treatment Period | Baseline of Period 1 | 6.7 Units on a scale | Standard Deviation 1.55 |
| Naproxen Followed by PF-04191834 + Naproxen | Daily Diary Pain Score During Week 2 of Each Treatment Period | Baseline of Period 2 | 5.6 Units on a scale | Standard Deviation 1.85 |
Comparison: The analysis was a mixed model with random participant effect, period and treatment as fixed effects, utilizing the baseline scores (one for each treatment period) as inter- and intra- participant covariates.80% CI: [-0.12, 0.31]ANCOVA
Comparison: The analysis was a mixed model with random participant effect, period and treatment as fixed effects, utilizing the baseline scores (one for each treatment period) as inter- and intra- participant covariates.80% CI: [-0.11, 0.31]ANCOVA
Secondary
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.
Time frame: 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
Population: Full Analysis Set (FAS): included all participants randomized who received at least one dose of study drug, regardless of whether they had efficacy data.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| PF-04191834 Followed by Placebo | Importance Weighted Total WOMAC Score | Period 1 Baseline | 19.7 Units on a scale | Standard Deviation 4.38 |
| PF-04191834 Followed by Placebo | Importance Weighted Total WOMAC Score | Period 1 End of Treatment | 18.3 Units on a scale | Standard Deviation 4.6 |
| PF-04191834 Followed by Placebo | Importance Weighted Total WOMAC Score | Period 2 Baseline | 17.0 Units on a scale | Standard Deviation 6.23 |
| PF-04191834 Followed by Placebo | Importance Weighted Total WOMAC Score | Period 2 End of Treatment | 14.4 Units on a scale | Standard Deviation 6.65 |
| Placebo Followed by PF-04191834 | Importance Weighted Total WOMAC Score | Period 1 End of Treatment | 18.2 Units on a scale | Standard Deviation 5.22 |
| Placebo Followed by PF-04191834 | Importance Weighted Total WOMAC Score | Period 2 Baseline | 16.2 Units on a scale | Standard Deviation 5.03 |
| Placebo Followed by PF-04191834 | Importance Weighted Total WOMAC Score | Period 2 End of Treatment | 15.6 Units on a scale | Standard Deviation 5.79 |
| Placebo Followed by PF-04191834 | Importance Weighted Total WOMAC Score | Period 1 Baseline | 20.5 Units on a scale | Standard Deviation 4.94 |
| PF-04191834 + Naproxen Followed by Naproxen | Importance Weighted Total WOMAC Score | Period 2 Baseline | 16.6 Units on a scale | Standard Deviation 5.25 |
| PF-04191834 + Naproxen Followed by Naproxen | Importance Weighted Total WOMAC Score | Period 1 End of Treatment | 15.9 Units on a scale | Standard Deviation 5.51 |
| PF-04191834 + Naproxen Followed by Naproxen | Importance Weighted Total WOMAC Score | Period 2 End of Treatment | 13.0 Units on a scale | Standard Deviation 5.29 |
| PF-04191834 + Naproxen Followed by Naproxen | Importance Weighted Total WOMAC Score | Period 1 Baseline | 19.4 Units on a scale | Standard Deviation 4.26 |
| Naproxen Followed by PF-04191834 + Naproxen | Importance Weighted Total WOMAC Score | Period 2 End of Treatment | 14.9 Units on a scale | Standard Deviation 7.71 |
| Naproxen Followed by PF-04191834 + Naproxen | Importance Weighted Total WOMAC Score | Period 1 End of Treatment | 16.6 Units on a scale | Standard Deviation 6.82 |
| Naproxen Followed by PF-04191834 + Naproxen | Importance Weighted Total WOMAC Score | Period 1 Baseline | 20.1 Units on a scale | Standard Deviation 5.17 |
| Naproxen Followed by PF-04191834 + Naproxen | Importance Weighted Total WOMAC Score | Period 2 Baseline | 18.4 Units on a scale | Standard Deviation 5.88 |
Comparison: The analysis was a mixed model with random participant effect, period and treatment as fixed effects, utilizing the baseline scores (one for each treatment period) as inter- and intra- participant covariates.80% CI: [-0.03, 1.58]ANCOVA
Comparison: The analysis was a mixed model with random participant effect, period and treatment as fixed effects, utilizing the baseline scores (one for each treatment period) as inter- and intra- participant covariates.80% CI: [-0.97, 0.65]ANCOVA
Secondary
Plasma Concentration of PF-04191834
Time frame: Pre-dose and post-dose (1 to 3 hours) on Days 1, 8, 15, 29, 36, and 43
Population: Due to early termination of the study, only a subset of pharmacokinetic (PK) samples, from 10 out of 190 randomized participants, were selected for analysis. These 10 participants were selected based on treatment and treatment sequence.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| PF-04191834 Followed by Placebo | Plasma Concentration of PF-04191834 | Period 1 Day 8 Post-dose | 511.0 ng/mL | Standard Deviation 246.07 |
| PF-04191834 Followed by Placebo | Plasma Concentration of PF-04191834 | Period 2 Day 29 Post-dose | 122.1 ng/mL | Standard Deviation 175.93 |
| PF-04191834 Followed by Placebo | Plasma Concentration of PF-04191834 | Period 1 Day 8 Pre-dose | 623.5 ng/mL | Standard Deviation 381.13 |
| PF-04191834 Followed by Placebo | Plasma Concentration of PF-04191834 | Period 1 Day 15 Pre-dose | 1007 ng/mL | Standard Deviation 61.518 |
| PF-04191834 Followed by Placebo | Plasma Concentration of PF-04191834 | Period 2 Day 36 Post-dose | 550.4 ng/mL | Standard Deviation 472.91 |
| PF-04191834 Followed by Placebo | Plasma Concentration of PF-04191834 | Period 2 Day 36 Pre-dose | 581.2 ng/mL | Standard Deviation 508.08 |
| PF-04191834 Followed by Placebo | Plasma Concentration of PF-04191834 | Period 2 Day 43 Pre-dose | 137.9 ng/mL | Standard Deviation 191.11 |
| PF-04191834 Followed by Placebo | Plasma Concentration of PF-04191834 | Period 1 Day 15 Post-dose | 797.5 ng/mL | Standard Deviation 171.83 |
| PF-04191834 Followed by Placebo | Plasma Concentration of PF-04191834 | Period 2 Day 43 Post-dose | 127.5 ng/mL | Standard Deviation 177.46 |
| PF-04191834 Followed by Placebo | Plasma Concentration of PF-04191834 | Period 1 Day 1 Post-dose | 121.5 ng/mL | Standard Deviation 7.7782 |
| Placebo Followed by PF-04191834 | Plasma Concentration of PF-04191834 | Period 2 Day 43 Post-dose | 1181 ng/mL | Standard Deviation 918.53 |
| Placebo Followed by PF-04191834 | Plasma Concentration of PF-04191834 | Period 1 Day 1 Post-dose | 214.8 ng/mL | Standard Deviation 280.61 |
| Placebo Followed by PF-04191834 | Plasma Concentration of PF-04191834 | Period 1 Day 8 Pre-dose | 1155 ng/mL | Standard Deviation 236.32 |
| Placebo Followed by PF-04191834 | Plasma Concentration of PF-04191834 | Period 1 Day 8 Post-dose | 1117 ng/mL | Standard Deviation 209.29 |
| Placebo Followed by PF-04191834 | Plasma Concentration of PF-04191834 | Period 1 Day 15 Pre-dose | 843.0 ng/mL | Standard Deviation 509.31 |
| Placebo Followed by PF-04191834 | Plasma Concentration of PF-04191834 | Period 1 Day 15 Post-dose | 736.0 ng/mL | Standard Deviation 440.86 |
| Placebo Followed by PF-04191834 | Plasma Concentration of PF-04191834 | Period 2 Day 29 Post-dose | 137.3 ng/mL | Standard Deviation 67.458 |
| Placebo Followed by PF-04191834 | Plasma Concentration of PF-04191834 | Period 2 Day 36 Pre-dose | 1141 ng/mL | Standard Deviation 918.53 |
| Placebo Followed by PF-04191834 | Plasma Concentration of PF-04191834 | Period 2 Day 36 Post-dose | 1154 ng/mL | Standard Deviation 787.01 |
| Placebo Followed by PF-04191834 | Plasma Concentration of PF-04191834 | Period 2 Day 43 Pre-dose | 1271 ng/mL | Standard Deviation 847.11 |
Secondary
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.
Time frame: Day -7 (Visit 2) up to 28-day follow-up (Visit 10)
Population: Number of subjects analyzed (N) is the number of participants taking rescue mediation.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| PF-04191834 Followed by Placebo | Rescue Medication Use | Period 2 | 1100.0 Number of pills | Standard Deviation 528.15 |
| PF-04191834 Followed by Placebo | Rescue Medication Use | Period 1 | 1096.1 Number of pills | Standard Deviation 310.59 |
| Placebo Followed by PF-04191834 | Rescue Medication Use | Period 2 | 1078.1 Number of pills | Standard Deviation 200.62 |
| Placebo Followed by PF-04191834 | Rescue Medication Use | Period 1 | 1114.5 Number of pills | Standard Deviation 367.92 |
| PF-04191834 + Naproxen Followed by Naproxen | Rescue Medication Use | Period 1 | 1210.2 Number of pills | Standard Deviation 442.7 |
| PF-04191834 + Naproxen Followed by Naproxen | Rescue Medication Use | Period 2 | 980.8 Number of pills | Standard Deviation 360.29 |
| Naproxen Followed by PF-04191834 + Naproxen | Rescue Medication Use | Period 2 | 932.7 Number of pills | Standard Deviation 263.27 |
| Naproxen Followed by PF-04191834 + Naproxen | Rescue Medication Use | Period 1 | 1073.7 Number of pills | Standard Deviation 409.83 |
Secondary
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.
Time frame: Day -7 (Visit 2) up to Day 43 (Visit 9 or End of Treatment Period 2)
Population: Since the study was terminated prematurely for a potential safety signal, and in light of the efficacy analysis, the pharmacodynamic (PD) assessment of uLTE4 was not performed and no data are reportable.
Secondary
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.
Time frame: 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
Population: Full Analysis Set (FAS): included all participants randomized who received at least one dose of study drug, regardless of whether they had efficacy data.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| PF-04191834 Followed by Placebo | WOMAC Physical Function Domain Score | Period 2 End of Treatment | 27.9 Units on a scale | Standard Deviation 13.11 |
| PF-04191834 Followed by Placebo | WOMAC Physical Function Domain Score | Period 1 Baseline | 37.7 Units on a scale | Standard Deviation 9.39 |
| PF-04191834 Followed by Placebo | WOMAC Physical Function Domain Score | Period 2 Baseline | 32.6 Units on a scale | Standard Deviation 12.37 |
| PF-04191834 Followed by Placebo | WOMAC Physical Function Domain Score | Period 1 End of Treatment | 35.4 Units on a scale | Standard Deviation 9.6 |
| Placebo Followed by PF-04191834 | WOMAC Physical Function Domain Score | Period 2 Baseline | 31.6 Units on a scale | Standard Deviation 9.64 |
| Placebo Followed by PF-04191834 | WOMAC Physical Function Domain Score | Period 2 End of Treatment | 30.8 Units on a scale | Standard Deviation 11.02 |
| Placebo Followed by PF-04191834 | WOMAC Physical Function Domain Score | Period 1 End of Treatment | 35.7 Units on a scale | Standard Deviation 10.01 |
| Placebo Followed by PF-04191834 | WOMAC Physical Function Domain Score | Period 1 Baseline | 39.7 Units on a scale | Standard Deviation 10.27 |
| PF-04191834 + Naproxen Followed by Naproxen | WOMAC Physical Function Domain Score | Period 2 Baseline | 31.6 Units on a scale | Standard Deviation 10.7 |
| PF-04191834 + Naproxen Followed by Naproxen | WOMAC Physical Function Domain Score | Period 1 End of Treatment | 30.8 Units on a scale | Standard Deviation 11.3 |
| PF-04191834 + Naproxen Followed by Naproxen | WOMAC Physical Function Domain Score | Period 1 Baseline | 37.4 Units on a scale | Standard Deviation 8.5 |
| PF-04191834 + Naproxen Followed by Naproxen | WOMAC Physical Function Domain Score | Period 2 End of Treatment | 25.0 Units on a scale | Standard Deviation 10.75 |
| Naproxen Followed by PF-04191834 + Naproxen | WOMAC Physical Function Domain Score | Period 1 Baseline | 38.7 Units on a scale | Standard Deviation 10.43 |
| Naproxen Followed by PF-04191834 + Naproxen | WOMAC Physical Function Domain Score | Period 2 End of Treatment | 28.7 Units on a scale | Standard Deviation 14.95 |
| Naproxen Followed by PF-04191834 + Naproxen | WOMAC Physical Function Domain Score | Period 1 End of Treatment | 32.0 Units on a scale | Standard Deviation 13.43 |
| Naproxen Followed by PF-04191834 + Naproxen | WOMAC Physical Function Domain Score | Period 2 Baseline | 35.6 Units on a scale | Standard Deviation 11.46 |
Comparison: The analysis was a mixed model with random participant effect, period and treatment as fixed effects, utilizing the baseline scores (one for each treatment period) as inter- and intra- participant covariates.80% CI: [-0.34, 2.85]ANCOVA
Comparison: The analysis was a mixed model with random participant effect, period and treatment as fixed effects, utilizing the baseline scores (one for each treatment period) as inter- and intra- participant covariates.80% CI: [-1.95, 1.28]ANCOVA
Secondary
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.
Time frame: 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
Population: Full Analysis Set (FAS): included all participants randomized who received at least one dose of study drug, regardless of whether they had efficacy data.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| PF-04191834 Followed by Placebo | WOMAC Stiffness Domain Score | Period 1 Baseline | 4.8 Units on a scale | Standard Deviation 1.2 |
| PF-04191834 Followed by Placebo | WOMAC Stiffness Domain Score | Period 1 End of Treatment | 4.4 Units on a scale | Standard Deviation 1.28 |
| PF-04191834 Followed by Placebo | WOMAC Stiffness Domain Score | Period 2 Baseline | 4.2 Units on a scale | Standard Deviation 1.51 |
| PF-04191834 Followed by Placebo | WOMAC Stiffness Domain Score | Period 2 End of Treatment | 3.3 Units on a scale | Standard Deviation 1.65 |
| Placebo Followed by PF-04191834 | WOMAC Stiffness Domain Score | Period 1 End of Treatment | 4.4 Units on a scale | Standard Deviation 1.44 |
| Placebo Followed by PF-04191834 | WOMAC Stiffness Domain Score | Period 2 Baseline | 3.9 Units on a scale | Standard Deviation 1.33 |
| Placebo Followed by PF-04191834 | WOMAC Stiffness Domain Score | Period 2 End of Treatment | 3.5 Units on a scale | Standard Deviation 1.38 |
| Placebo Followed by PF-04191834 | WOMAC Stiffness Domain Score | Period 1 Baseline | 5.0 Units on a scale | Standard Deviation 1.41 |
| PF-04191834 + Naproxen Followed by Naproxen | WOMAC Stiffness Domain Score | Period 2 Baseline | 3.9 Units on a scale | Standard Deviation 1.44 |
| PF-04191834 + Naproxen Followed by Naproxen | WOMAC Stiffness Domain Score | Period 1 End of Treatment | 3.8 Units on a scale | Standard Deviation 1.36 |
| PF-04191834 + Naproxen Followed by Naproxen | WOMAC Stiffness Domain Score | Period 2 End of Treatment | 2.9 Units on a scale | Standard Deviation 1.31 |
| PF-04191834 + Naproxen Followed by Naproxen | WOMAC Stiffness Domain Score | Period 1 Baseline | 4.7 Units on a scale | Standard Deviation 1.42 |
| Naproxen Followed by PF-04191834 + Naproxen | WOMAC Stiffness Domain Score | Period 2 End of Treatment | 3.6 Units on a scale | Standard Deviation 1.74 |
| Naproxen Followed by PF-04191834 + Naproxen | WOMAC Stiffness Domain Score | Period 1 End of Treatment | 4.0 Units on a scale | Standard Deviation 1.55 |
| Naproxen Followed by PF-04191834 + Naproxen | WOMAC Stiffness Domain Score | Period 1 Baseline | 4.8 Units on a scale | Standard Deviation 1.47 |
| Naproxen Followed by PF-04191834 + Naproxen | WOMAC Stiffness Domain Score | Period 2 Baseline | 4.4 Units on a scale | Standard Deviation 1.41 |
Comparison: The analysis was a mixed model with random participant effect, period and treatment as fixed effects, utilizing the baseline scores (one for each treatment period) as inter- and intra- participant covariates.80% CI: [-0.15, 0.29]ANCOVA
Comparison: The analysis was a mixed model with random participant effect, period and treatment as fixed effects, utilizing the baseline scores (one for each treatment period) as inter- and intra- participant covariates.80% CI: [-0.09, 0.35]ANCOVA
Secondary
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.
Time frame: 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
Population: Full Analysis Set (FAS): included all participants randomized who received at least one dose of study drug, regardless of whether they had efficacy data.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| PF-04191834 Followed by Placebo | WOMAC Total Score | Period 1 Baseline | 53.7 Units on a scale | Standard Deviation 11.96 |
| PF-04191834 Followed by Placebo | WOMAC Total Score | Period 1 End of Treatment | 50.0 Units on a scale | Standard Deviation 12.6 |
| PF-04191834 Followed by Placebo | WOMAC Total Score | Period 2 Baseline | 46.4 Units on a scale | Standard Deviation 16.94 |
| PF-04191834 Followed by Placebo | WOMAC Total Score | Period 2 End of Treatment | 39.4 Units on a scale | Standard Deviation 18.13 |
| Placebo Followed by PF-04191834 | WOMAC Total Score | Period 1 End of Treatment | 49.9 Units on a scale | Standard Deviation 14.16 |
| Placebo Followed by PF-04191834 | WOMAC Total Score | Period 2 Baseline | 44.2 Units on a scale | Standard Deviation 13.62 |
| Placebo Followed by PF-04191834 | WOMAC Total Score | Period 2 End of Treatment | 42.6 Units on a scale | Standard Deviation 15.73 |
| Placebo Followed by PF-04191834 | WOMAC Total Score | Period 1 Baseline | 56.0 Units on a scale | Standard Deviation 13.49 |
| PF-04191834 + Naproxen Followed by Naproxen | WOMAC Total Score | Period 2 Baseline | 45.1 Units on a scale | Standard Deviation 14.37 |
| PF-04191834 + Naproxen Followed by Naproxen | WOMAC Total Score | Period 1 End of Treatment | 43.5 Units on a scale | Standard Deviation 14.96 |
| PF-04191834 + Naproxen Followed by Naproxen | WOMAC Total Score | Period 2 End of Treatment | 35.4 Units on a scale | Standard Deviation 14.32 |
| PF-04191834 + Naproxen Followed by Naproxen | WOMAC Total Score | Period 1 Baseline | 52.9 Units on a scale | Standard Deviation 11.57 |
| Naproxen Followed by PF-04191834 + Naproxen | WOMAC Total Score | Period 2 End of Treatment | 40.6 Units on a scale | Standard Deviation 20.99 |
| Naproxen Followed by PF-04191834 + Naproxen | WOMAC Total Score | Period 1 End of Treatment | 45.4 Units on a scale | Standard Deviation 18.54 |
| Naproxen Followed by PF-04191834 + Naproxen | WOMAC Total Score | Period 1 Baseline | 54.8 Units on a scale | Standard Deviation 14.05 |
| Naproxen Followed by PF-04191834 + Naproxen | WOMAC Total Score | Period 2 Baseline | 50.3 Units on a scale | Standard Deviation 15.96 |
Comparison: The analysis was a mixed model with random participant effect, period and treatment as fixed effects, utilizing the baseline scores (one for each treatment period) as inter- and intra- participant covariates.80% CI: [-0.13, 4.25]ANCOVA
Comparison: The analysis was a mixed model with random participant effect, period and treatment as fixed effects, utilizing the baseline scores (one for each treatment period) as inter- and intra- participant covariates.80% CI: [-2.53, 1.88]ANCOVA