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    Summary
    EudraCT Number:2011-004179-35
    Sponsor's Protocol Code Number:OSKNEEPA02
    National Competent Authority:Denmark - DHMA
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2011-11-28
    Trial results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedDenmark - DHMA
    A.2EudraCT number2011-004179-35
    A.3Full title of the trial
    A single center, randomized, double-blind, placebo-controlled 2-way crossover study to investigate the mechanism of action of etoricoxib in subjects with osteoarthritis knee pain
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A single center, randomized, double-blind, placebo-controlled 2-way crossover study to investigate the mechanism of action of etoricoxib in subjects with osteoarthritis knee pain
    A.3.2Name or abbreviated title of the trial where available
    OSKNEEPA02
    A.4.1Sponsor's protocol code numberOSKNEEPA02
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorC4Pain ApS
    B.1.3.4CountryDenmark
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportMerck, Sharp & Dohme Corp.
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationCCBR A/S
    B.5.2Functional name of contact pointBettina Storgaard Nedergaard
    B.5.3 Address:
    B.5.3.1Street AddressHobrovej 42D, 2.
    B.5.3.2Town/ cityAalborg
    B.5.3.3Post code9000
    B.5.3.4CountryDenmark
    B.5.4Telephone number004598129048
    B.5.5Fax number004598139048
    B.5.6E-mailbettina.nedergaard@ccbr.com
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name Arcoxia
    D.2.1.1.2Name of the Marketing Authorisation holderMerck, Sharp & Dohme B.V.
    D.2.1.2Country which granted the Marketing AuthorisationNetherlands
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.4Pharmaceutical form Coated tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboCoated tablet
    D.8.4Route of administration of the placeboOral use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Osteoarthritic Knee Pain.
    E.1.1.1Medical condition in easily understood language
    Pain in the knee caused by osteoarthrosis.
    E.1.1.2Therapeutic area Diseases [C] - Musculoskeletal Diseases [C05]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 14.1
    E.1.2Level LLT
    E.1.2Classification code 10029877
    E.1.2Term OA knee
    E.1.2System Organ Class 10028395 - Musculoskeletal and connective tissue disorders
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    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.
    E.2.2Secondary objectives of the trial
    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.
    E.2.3Trial contains a sub-study No
    E.3Principal 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 (index knee) diagnosed in accordance with the American College of Rheumatology (ACR) 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):
    a. Knee pain for at least 14 days per month for the 3 months before study entry.
    b. Osteophytes (with radiographic evidence).
    c. And at least 1 of the following 3 conditions: Age >50, or morning stiffness <30 minutes, or crepitus.
    d. 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 (i.e. days -14 to day -1) 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 [OTC] analgesics/ Non-Steroidal Anti-Inflammatory Drug (NSAID) at least 3 days prior to visit 2 (subjects are allowed limited use of analgesic medications, refer to section on Permissible Medications/Treatments).
    7.Have agreed to maintain the same activity level throughout the course of the study.
    E.4Principal exclusion criteria
    Have a history of recurrent seizures other than febrile seizures, or a history of frequent and/or severe allergic reactions with multiple medications.
    Have a current or recent history 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.
    At screening, have an abnormality in the 12-lead ECG that increases the risks associated with participation in the study. In addition, subjects with following findings will be excluded:
    a. Confirmed Bazett’s corrected QT (QTcB) interval > 450 msec for men and > 470 msec for women at screening.
    b. 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,
    c. Irregular rhythms other than sinus arrhythmia or occasional supraventricular or ventricular ectopic beats,
    d. History of unexplained syncope. Family history of unexplained sudden death or sudden death due to long QT syndrome,
    f. T-wave configurations are not of sufficient quality for assessing QT interval determination.
    Have an ALAT >2.5 timer ULN at screening.
    Have prior renal transplant, current renal dialysis or severe renal insufficiency ( determined by GFR), or serum creatinine laboratory value >1.5 times ULN.

    Have active peptic ulcer or gastrointestinal (GI) bleeding.
    Have known inflammatory intestinal disease.
    Subject with ischemic heart disease, peripheral arterial disease and/or cerebrovascular disease or with congestive heart failure (NYHA II-IV).
    Subject with uncontrolled arterial hypertension (>160/90) diabetes mellitus and atherosclerosis.
    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.
    Allergic to the active ingredient of etoricoxib or one or more of the excipients.
    Pregnant female or breast feeding.
    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).
    Are taking any excluded medications (analgesic medications) that cannot be discontinued during the screening period (3 days prior to visit 2).
    Subject in treatment with anticoagulants (with the exception of acetylsalicylic acid), methotrexate or rifampicin or antihypertensiva (with the exception of Ca+-antagonists).
    Have received treatment within the last 30 days with an investigational study drug
    Have a history of substance abuse or dependence within the past year, excluding nicotine and caffeine.
    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).
    Subject with a history of, or suspected, demyelinating disease of the central nervous system (e.g. multiple sclerosis or optic neuritis).
    Have an autoimmune disorder (not including psoriasis).
    Subject that do not fully understand the EPM procedures according to investigator experience.

    Investigator site personnel directly affiliated with this study and/or their immediate family cannot participate.

    Subject diagnosed with any condition suggestive of a secondary cause of knee OA.
    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.
    History of significant prior injury to the index knee within 12 months prior to visit 1.
    Subject diagnosed with Kellgren and Lawrence grade IV at the index knee.
    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.
    History of prior synovial fluid analysis showing a WBC count ≥2000mm3 .
    Have a confounding painful condition that may interfere with assessment of the index knee joint.
    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).
    Intra-articular injection and intra-muscular corticosteroid injection within 3 months, oral corticosteroids within 1 month to baseline.
    Have initiated or changed their established physiotherapy program within the last 14 day prior to visit 3, or have not completed 10 days out of 14 days diary.
    E.5 End points
    E.5.1Primary end point(s)
    As the primary objective of this study is assessment of which pain mechanisms are modulated by study drug administration, the primary endpoints will include Experimental mechanism based Pain Measures (EPMs) as listed below:
    • Quantitative Sensory Testing (QST) of joint pain (pressure pain thresholds from 3 knee joint locations of most painful side)
    • Spreading sensitization (pressure pain threshold from tibialis anterior of the most painful knee and from the extensor carpi radialis longus muscle on the ipsilateral site)
    • Pain areas (area of pain drawings)
    • Wind-up like pain (repeated mechanical pressure stimulation to the most painful knee site and tibialis anterior muscle)
    • Descending noxious inhibitory control (combining pressure pain at the knee, leg and arm and pressure pain to cuff inflation)
    • Cuff evoked pain (cuff algometry)
    • Infrared thermography of both knees (medial, frontal and lateral views)
    E.5.1.1Timepoint(s) of evaluation of this end point
    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.
    Pain Models (EPMs) to be performed at: visit 3, 5, 6 and 8
    E.5.2Secondary end point(s)
    Change of pain severity from baseline to end of study, as measured by the weekly mean of the daily 24-hour average pain score (APS), night pain and worst daily pain, Pain Quality Assessment Scale (PQAS), Brief Pain Inventory (BPI), Investigator and Patient Global Assessment of Changes (IGIC and PGAC), Western Ontario and McMaster (WOMAC) OA physical function, time and pain intensity from the 40 m self-paced walk test, time and pain intensity from the 11 step stair climb test, DoloTest® and PainDetect.
    Fasting plasma, serum and urine samples will be collected and stored for potential further analysis of e.g. IL-6, IL-8, CTX1, CTX2, TNFα, CCL2, CO1, CO2, sCRP, CRP25, C1M, C2M, C3M, OC, MMP.
    E.5.2.1Timepoint(s) of evaluation of this end point
    Timepoints for questionnaires:
    PQAS, IGIC and PGAC; visit 3, 4, 5, 6, 7, and 8
    BPI, WOMAC, self-paced walk test, stair climb test, DoloTest and PD-Q; visit 1, 3, 5, 6 and 8
    Inflammatory, bone and cartilage related bio-chemical biomarkers; visit 3, 5, 6 and 8
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy No
    E.6.4Safety Yes
    E.6.5Efficacy No
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others Yes
    E.6.13.1Other scope of the trial description
    Investigate if change in inflammatory, bone and cartilage related bio-chemical biomarkers can explain changes in either experimental or clinical pain parameters.
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group No
    E.8.1.6Cross over Yes
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo Yes
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial2
    E.8.3 The trial involves single site in the Member State concerned Yes
    E.8.4 The trial involves multiple sites in the Member State concerned No
    E.8.4.1Number of sites anticipated in Member State concerned1
    E.8.5The trial involves multiple Member States No
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.7Trial has a data monitoring committee No
    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
    LPLV
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years0
    E.8.9.1In the Member State concerned months12
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years0
    E.8.9.2In all countries concerned by the trial months12
    E.8.9.2In all countries concerned by the trial days0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 34
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 8
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state42
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2011-12-06
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2012-04-30
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2013-07-09
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