E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Chronic pain in patients with Osteo-arthritis. |
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MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 12.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10023476 |
E.1.2 | Term | Knee osteoarthritis |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
- To evaluate the efficacy of PF-04191834 versus placebo in relieving pain in patients with osteoarthritis of the knee. - To evaluate the efficacy of PF-04191834 plus naproxen versus naproxen in relieving pain in patients with osteoarthritis of the knee. - To evaluate the safety and tolerability of PF-04191834 (as monotherapy) in patients with osteoarthritis. - To evaluate the safety and tolerability of PF-04191834 when co-administered with naproxen in patients with osteoarthritis. |
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E.2.2 | Secondary objectives of the trial |
- To examine the pharmacokinetics of PF-04191834 in patients with osteoarthritis. - To explore the relationship between urinary LTE4 levels as a biomarker of 5-LO inhibition and efficacy of PF-04191834 in patients with osteoarthritis. - To provide samples for exploratory research into the mechanism of action of PF-04191834 and/or the disease (OA) under study. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Subject eligibility should be reviewed and documented by an appropriately qualified member of the investigator’s study team before subjects are included in the study. Subjects must meet all of the following inclusion criteria to be eligible for enrollment into the study: 1. Evidence of a personally signed and dated informed consent document indicating that the subject (or a legally acceptable representative) has been informed of all pertinent aspects of the study. 2. Male or female subjects between the ages of 18 and 75 years inclusive at the time of entering the study. 3. Diagnosis of OA of the knee based on American College of Rheumatology criteria with X-ray confirmation (a Kellgren-Lawrence X-ray grade of ≥229 with symptom duration for at least 3 months. X-rays taken within the last 12 months may be used for confirmation provided appropriate documentation is available. 4. Willing and able to discontinue all current analgesic therapy, including OTC pain medications and topical analgesics for OA pain, for period beginning at washout phase and continuing for the entire duration of study. 5. For subjects discontinuing background NSAIDs and COX-2 inhibitors only, an increase in NRS ≥1 during the placebo run-in prior to randomization at Visit 3. 6. Daily pain score ≥4 during the run-in in the last 3 daily diary assessments prior to randomization. 7. Subjects who are willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures. |
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E.4 | Principal exclusion criteria |
1. Body mass index (BMI) of >39 kg/m2. A BMI upper limit of 39.5 kg/m2 may be rounded down to 39.0 kg/m2 and will be acceptable for inclusion. 2. Clinical evidence of existing hepatic disease or a medical history of such a condition in the last year. Subjects with AST or ALT >ULN. Subjects with total bilirubin >ULN (except those with a documented history of Gilbert’s Syndrome). Subjects with AST/ALT/total bilitubin >ULN and <1.5X ULN may be retested once. 3. Pregnant or lactating females; females of childbearing potential who are unwilling or unable to use an acceptable method of non-hormonal contraception as outlined in this protocol from at least 14 days prior to the first dose of study medication through 28 days after the last dose of study drug. 4. Participation in a clinical trial for an investigational drug and/or agent within 30 days (or 5 half-lives, whichever is longer) prior to randomization. 5. Any history of alcohol or illicit drug abuse within 1 year of screening. 6. A positive urine drug screen. 7. Active malignancy of any type or history of a malignancy within 10 years (with the exception of subjects with a history of treated basal cell carcinoma or successful surgically treated stage 0/1 cervical cancer). 8. Symptomatic OA of the hip ipsilateral to index knee which the patient considers more painful than the knee. 9. Subjects with a history of HIV. 10. Subjects with a history of Hepatitis B or Hepatitis C infection, confirmed by hepatitis virus serology. 11. History of diseases other than OA that may involve the index knee, including: Inflammatory joint diseases, Crystalline diseases, Endocrinopathies, Metabolic diseases, Infections, Neuropathic disorders, Avascular necrosis, Paget’s disease, or Tumors, Symptomatic anserine bursitis or acute joint trauma of the index knee within 1 year, Arthroscopy performed on index knee within 1 year, Other severe pain that impairs the assessment of OA pain. 12. Any condition affecting drug absorption, eg, gastrectomy or any active GI disease (including any relevant surgery). 13. Active or history of peptic ulceration, erosive gastritis, gastrointestinal bleeding (two or more distinct episodes of proven ulceration or bleeding), or perforation. 14. Subjects with a history of coagulapathy or abnormal bleeding times. 15. Patients with uncontrolled hypertension, congestive heart failure, established ischemic heart disease, peripheral arterial disease, and/or cerebrovascular disease. Patients with resting heart rate >100 or <50 bpm, first degree or higher AV block, defined as PR interval >210 msec, complete left or right bundle branch block or other clinically significant conduction abnormality, evidence of prior myocardial infarction, evidence of QTc prolongation (defined as >450 msec) or history of QTc prolongation, or any other clinically relevant abnormality on screening ECG. - If QTc is prolonged with the singlet measurement, the ECG should be repeated two more times and the average QTc of all three readings should be used to qualify the subject. 16. Known or previously exhibited hypersensitivity to the active substance naproxen (including naproxen sodium) or any of the excipients. 17. Any history of asthma, urticaria, or allergic-type reactions after taking acetylsalicylic acid (ASA) or other NSAIDs (ie, complete or partial syndrome of ASA-intolerancerhinosinusitis, urticaria/angioedema, nasal polyps, asthma). 18. Use of prohibited medications as listed below, in the absence of appropriate washout period (greater of 2 days or 5 half-lives): NSAIDs and COX-2 inhibitors, Acetaminophen (as an exception acetaminophen may be used for non-joint related conditions at doses ≤1g/day at the discretion of a qualified member of the Pfizer study team.): Opioids, Aspirin >82 mg/day. Oral or IM corticosteroids within 4 weeks, IA steroids within 12 weeks in study joint or any other joints within 4 weeks, or IA hyaluronic acid within 24 weeks prior to baseline, Concomitant medications that are strong and moderate CYP3A inhibitors such as ketoconazole, itraconazole, saquinavir, or CYP3A inducers, Subjects that have previously received any 5-LO treatment (zileuton), Montelukast, pranlukast, zafirlukast, and any other leukotriene receptor antagonist. 19. Other severe acute or chronic medical or psychiatric conditions or pre-dispositions or laboratory abnormality that may increase the risk associated with study participation or investigational product administration or may interfere with interpretation of study results and, in the judgment of the investigator, would make the subject inappropriate for entry into this study eg, active tuberculosis. 20. Subjects with any personal or family history of psychosis. 21. Evidence of moderate or severe depression as determined by Hospital anxiety & depression scale (HADS) assessment. 22. Subjects with positive responses for suicidality on the Columbia Suicide-Severity Rating Scale (C-SSRS). |
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E.5 End points |
E.5.1 | Primary end point(s) |
Western Ontario & McMaster (WOMAC) Osteoarthritis Index (48 hour recall, categorical version) Pain Score (Likert Scale, Range 0-20) in the more painful knee joint as identified at screening at the end of treatment period relative to baseline as follows: PF-04191834 compared to placebo. PF-04191834 + naproxen compared to naproxen. |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | Yes |
E.8.1.7 | Other | Yes |
E.8.1.7.1 | Other trial design description |
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E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | Yes |
E.8.2.3.1 | Comparator description |
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E.8.3 |
The trial involves single site in the Member State concerned
| Information not present in EudraCT |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 2 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
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E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | |
E.8.9.1 | In the Member State concerned months | 8 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 0 |
E.8.9.2 | In all countries concerned by the trial months | 8 |
E.8.9.2 | In all countries concerned by the trial days | 0 |