A Single Center 2-way Crossover Study to Investigate the Mechanism of Action of Etoricoxib in Subjects With Osteoarthritis Knee Pain
A Single Center 2-way Crossover Study to Investigate the Mechanism of Action of Etoricoxib in Subjects With Osteoarthritis Knee Pain
The purpose of this study is to investigate which pain mechanisms that can be affected by
 etoricoxib compared to placebo (inactive medication)in subjects with painful knee
 osteoarthritis af 4 weeks of treatment.
Study Rationale: The purpose of this study is to investigate which pain mechanisms in
 subjects with painful knee osteoarthritis can be affected by the peripheral and central
 actions of etoricoxib as compared to placebo during a 4 week treatment therapy period.

 The present study will utilize a set of quantitative mechanism based pain biomarkers to
 assess peripheral and central pain manifestations in OA and the influence of etoricoxib on
 those individual manifestations in an attempt to understand and explain clinical pain
 alleviation.

 Study Treatment: Subjects will be randomized to one of the 2 sequences of treatment: Sequence
 1 (60 mg/day etoricoxib followed by placebo) or Sequence 2 (placebo followed by 60 mg/day
 etoricoxib). The two treatment periods of 4 weeks each are separated by a washout period of
 at least 6 days.

 Primary Objective: To assess which pain mechanisms are modulated by 60 mg daily
 administration of etoricoxib compared to placebo in subjects with osteoarthritic (OA) knee
 pain during two treatment periods of 4-weeks each.

 Secondary Objectives: To evaluate if changes in any of the mechanism based experimental pain
 assessment parameters can explain changes in clinical outcome parameters.

 To profile drug responders- versus non-responders based on pain mechanisms involved.

 To investigate if change in inflammatory, bone and cartilage related bio-chemical biomarkers
 can explain changes in either experimental or clinical pain parameters.
Inclusion Criteria:

 1. Written informed consent (IRB/IEC specific) has been obtained prior to initiation of
 any protocol required procedures.

 2. Male or female between 40 and 75 years of age. Females of childbearing potential must
 have a negative urine pregnancy test at screening.

 3. Body weight >40 kg and <150 kg with a body mass index (BMI) between 19-40 kg/m2
 inclusive.

 4. Idiopathic osteoarthritic knee pain diagnosed in accordance with the American College
 of Rheumatology modified clinical classification criteria (Altman et al, 1986) and
 verified radiologically as Kellgren-Lawrence grade I, II or III (Kellgren and
 Lawrence, 1957) at the index knee. The clinical diagnosis of OA will be confirmed by
 the ACR clinical and radiographic criteria for classification of idiopathic OA based
 upon the following criteria (index knee):

 1. Knee pain for at least 14 days per month for the 3 months before study entry.

 2. Osteophytes (with radiographic evidence).

 3. And at least 1 of the following 3 conditions: Age >50, or morning stiffness <30
 minutes, or crepitus.

 4. X-ray images of the knee joints are available confirming OA. X-ray images older
 than12 months cannot be used. New photos are needed to confirm the diagnostic
 criteria for OA.

 5. For the index knee, the average of the worst daily pain score over the last 14 days
 prior to day 0 must be 4.0 to 9.0. The 14-day average score will be derived from worst
 daily pain scores recorded in a diary for the index knee.

 6. Discontinued use of all analgesic medications (including over-the-counter analgesics/
 Non-Steroidal Anti-Inflammatory Drug at least 3 days prior to visit 2 (subjects are
 allowed limited use of analgesic medications).

 7. Have agreed to maintain the same activity level throughout the course of the study.

 Exclusion Criteria:

 1. Have a history of recurrent seizures other than febrile seizures.

 2. Have a history of frequent and/or severe allergic reactions with multiple medications.

 3. Have a current or recent history, as determined by the investigator or his delegates,
 of severe, progressive, and/or uncontrolled renal, hepatic, hematological,
 gastrointestinal, endocrine, pulmonary, cardiac, neurological, psychiatric or cerebral
 disease which could interfere with the subject's participation in the study.

 4. At screening, have an abnormality in the 12-lead ECG that, in the opinion of the
 investigator, increases the risks associated with participation in the study. In
 addition, subjects with following findings will be excluded:

 1. Confirmed Bazett's corrected QT (QTcB) interval > 450 msec for men and > 470 msec
 for women at screening. If QTcB is prolonged a second ECG will be taken to
 confirm the finding; (additional ECGs may be performed if required),

 2. Bundle branch blocks and other conduction abnormalities other than mild first
 degree atrio-ventricular block, left anterior hemi block due to left axis
 deviation and right bundle branch block of benign origin i.e. not caused by other
 cardiac disease,

 3. Irregular rhythms other than sinus arrhythmia or occasional supraventricular or
 ventricular ectopic beats,

 4. History of unexplained syncope,

 5. Family history of unexplained sudden death or sudden death due to long QT
 syndrome,

 6. T-wave configurations are not of sufficient quality for assessing QT interval
 determination, as assessed by the investigator.

 5. Have an alanine aminotransaminase > 2.5 times Upper Limit of Normal (ULN) at
 screening, based on reference ranges of the local laboratory. Moderate or greater
 hepatic impairment.

 6. Have prior renal transplant, current renal dialysis or severe renal insufficiency
 (determined by a derived glomerular filtration rate using Cockcroft Gault formula of
 ≤30 ml/min/1,73m² calculated by the local lab), or serum creatinine laboratory value
 >1.5 times ULN, based on the reference ranges of the local laboratory.

 7. Have active peptic ulcer or gastrointestinal bleeding.

 8. Have known inflammatory intestinal disease.

 9. Subject with ischemic heart disease, peripheral arterial disease and/or
 cerebrovascular disease.

 10. Subject with congestive heart failure (NYHA II-IV).

 11. Subject with uncontrolled arterial hypertension (>160/90).

 12. Subject with diabetes mellitus and documented atherosclerosis.

 13. History of bronchospasms, acute rhinitis, nasal polyps, angioneurotic edema, urticaria
 or other type of allergic reaction after having used acetylic acid or NSAID, inclusive
 COX-2 inhibitors.

 14. Is allergic to the active ingredient of etoricoxib or one or more of the excipients.

 15. Pregnant female, breast feeding or planning a pregnancy during the study period.
 Females of child-bearing potential, not using a reliable means of contraception.

 16. Subject with an active malignancy of any type or a history of malignancy within the
 last 5 years (except basal cell carcinoma of the skin that has been excised prior to
 study start).

 17. Are taking any excluded medications (analgesic medications) that cannot be
 discontinued during the screening period (3 days prior to visit 2).

 18. Subject in treatment with anticoagulants (with the exception of acetylsalicylic acid),
 methotrexate or rifampicin or antihypertensives (with the exception of
 Ca+-antagonists).

 19. Have received treatment within the last 30 days with a drug that has not received
 regulatory approval for any indication at Visit 1.

 20. Have a history of substance abuse or dependence within the past year, excluding
 nicotine and caffeine.

 21. Subject at a high risk of infection (e.g. leg ulcers, indwelling urinary catheter and
 persistent or recurrent chest infections and subjects who are permanently bed ridden
 or wheelchair bound).

 22. Subject with a history of, or suspected, demyelinating disease of the central nervous
 system (e.g. multiple sclerosis or optic neuritis).

 23. Have an autoimmune disorder (not including psoriasis).

 24. Subject that do not fully understand the EPM procedures according to investigator
 experience.

 25. Investigator site personnel directly affiliated with this study and/or their immediate
 family cannot participate. Immediate family is defined as a spouse, parent, child, or
 sibling, whether biological or legally adopted.

 26. Subject diagnosed with any condition suggestive of a secondary cause of knee OA
 including but not limited to knee trauma, septic arthritis, inflammatory joint
 disease, articular fracture, major dysplasia or congenital abnormality, ochronosis,
 acromegaly, hemochromatosis, Wilson's disease, or primary osteochondromatosis.

 27. History of surgery (including arthroscopy) in the index knee within 3 months prior to
 visit 1 or already planned surgery of the index knee at any time.

 28. History of significant prior injury to the index knee within 12 months prior to visit
 1.

 29. Subject diagnosed with Kellgren and Lawrence grade IV at the index knee.

 30. Use of lower extremity assistive devices other than a knee brace or 'shoe lift'. Use
 of a cane in the hand opposite to the index knee is acceptable.

 31. History of prior synovial fluid analysis showing a White Blood Cell count ≥ 2000 mm3
 that is indicative of a diagnosis other than OA at the index knee.

 32. Have a confounding painful condition that may interfere with assessment of the index
 knee joint. (Knee pain should be the predominant pain. Mild OA of the hands is
 allowed, for instance).

 33. History of any other musculoskeletal or arthritic condition that may affect the
 interpretation of clinical efficacy and/or safety data or otherwise contraindicates
 participation in this clinical study (i.e., currently symptomatic fractures or any
 concurrent rheumatic disease such as but not limited to fibromyalgia, rheumatoid
 arthritis, gout, pseudo-gout or Paget's disease and Reiter's syndrome are excluded).

 34. Have used corticosteroids prior to baseline:

 1. Intra-articular injection of steroids into the index knee or into any other site
 than the index knee within the previous 3 months,

 2. Intra-muscular corticosteroid injections within the previous 3 months,

 3. Oral corticosteroids within the previous 1 month.

 35. Have initiated or changed their established physiotherapy program within the last 14
 day prior to visit 3.

 36. Have not recorded a minimum of 10 days of diary data of the last 14 days immediately
 preceding visit 3.