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    Summary
    EudraCT Number:2012-003770-11
    Sponsor's Protocol Code Number:GROSKNEEPA01
    National Competent Authority:Denmark - DHMA
    Clinical Trial Type:EEA CTA
    Trial Status:Prematurely Ended
    Date on which this record was first entered in the EudraCT database:2012-11-26
    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 number2012-003770-11
    A.3Full title of the trial
    A multi-center, randomized parallel group pilot study to investigate the mechanism of action of tapentadol PR and oxycodone CR in subjects with osteoarthritis knee pain
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A multi-center, randomized parallel group pilot study to investigate the mechanism of action of tapentadol PR and oxycodone CR in subjects with osteoarthritis knee pain
    A.3.2Name or abbreviated title of the trial where available
    GROSKNEEPA01
    A.4.1Sponsor's protocol code numberGROSKNEEPA01
    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 supportGrünenthal GmbH
    B.4.2CountryGermany
    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 number004596334720
    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 Palexia Depot
    D.2.1.1.2Name of the Marketing Authorisation holderGrünenthal GmbH
    D.2.1.2Country which granted the Marketing AuthorisationGermany
    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 Tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNTapentadol
    D.3.9.1CAS number 175591-23-8
    D.3.9.2Current sponsor codePalexia SR
    D.3.9.3Other descriptive nameTAPENTADOL
    D.3.9.4EV Substance CodeSUB31821
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typerange
    D.3.10.3Concentration number100 to 500
    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.IMP: 2
    D.1.2 and D.1.3IMP RoleComparator
    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 OxyContin
    D.2.1.1.2Name of the Marketing Authorisation holderNorpharma a/s
    D.2.1.2Country which granted the Marketing AuthorisationDenmark
    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 Tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNOXYCODONE
    D.3.9.1CAS number 76-42-6
    D.3.9.2Current sponsor codeOxyContin
    D.3.9.3Other descriptive nameOXYCODONE
    D.3.9.4EV Substance CodeSUB09562MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typerange
    D.3.10.3Concentration number20 to 100
    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
    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 18.0
    E.1.2Level LLT
    E.1.2Classification code 10029877
    E.1.2Term OA knee
    E.1.2System Organ Class 100000004859
    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 (with specific focus on the descending inhibition) are modulated by daily administration of 2 x 100-250 mg tapentadol PR compared to 2 x 20-50 mg oxycodone CR in subjects with osteoarthritic (OA) knee pain during a treatment period of 4-weeks (preceded to a titration period of up to 15 days).
    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 (reduction in clinical pain intensity).
    To profile drug responders- versus non-responders based on pain mechanisms involved.
    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 80 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 5.0 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
    1. A history of recurrent seizures other than febrile seizures.
    2. A history of frequent and/or severe allergic reaction with multiple medication.
    3. A current or recent history, as determined by the investigator or his delegates, of severe, progressive, and/or uncontrolled renal, including severe renal impairment, hepatic, including severe impaired liver function, hematological, gastrointestinal, endocrine, pulmonary, including respiratory depression, COPD or acute severe asthma, cardiac, including cor pulmonale, 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:
    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: i) mild first degree atrio-ventricular block, ii) left anterior hemi block due to left axis deviation, iii) 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,
    e. 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, as assessed by the investigator.
    5. An alanine aminotransaminase. Moderate or greater hepatic impairment.
    6. Prior renal transplant, current renal dialysis or severe renal insufficiency or serum creatinine.
    7. Pregnant female, breast feeding or planning a pregnancy during the study period. Females of child-bearing potential, not using a reliable means of contraception (refer to section 8.5.3 – reliable contraception).
    8. 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).
    9. Any excluded medications (analgesic medications) that cannot be discontinued during the screening period (3 days prior to visit 2).
    10. Treatment within the last 30 days with a drug that has not received regulatory approval.
    11. Substance abuse or dependence, not nicotine/caffeine.
    12. A high risk of infection.
    13. A history of, or suspected, demyelinating disease of the central nervous system.
    14. An autoimmune disorder.
    15. Not fully understand the EPM procedures.
    16. Investigator site personnel directly affiliated with this study and/or their immediate family.
    17. Diagnosed with any condition suggestive of a secondary cause of knee OA.
    18. History of surgery in the index knee within 3 months or planned surgery.
    19. Complicated prior injury to the index knee within 12 months.
    20. Diagnosed with Kellgren and Lawrence grade 0 or IV.
    21. Use of lower extremity assistive devices.
    22. Prior synovial fluid analysis showing a WBC≥2000mm.
    23. A confounding painful condition that may interfere with assessment.
    24. 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.
    25. Have used corticosteroids prior to baseline: a. Intra-articular injection of steroids into the index knee or into any other site than the index knee within the previous 3 months; b. Intra-muscular corticosteroid injections within the previous 3 months; c. Oral corticosteroids within the previous 1 month.
    26. Initiated or changed their established physiotherapy program within the last 14 day prior to visit 3.
    27. Not recorded a minimum of 10 days of diary data of the last 14 days immediately preceding visit 3.
    28. Currently on strong opioids or have been within the past 3 months. .
    29. Increased intracranial pressure, hypovolemia, symptomatic hypotension, prostatism, Untreated hypothyroidism, paralytic ileus or pancreatitis.
    30. Treatment with MAO-inhibitors, rifampicin and CNS depressants (e.g. benzodiazepines, barbiturates, phenytoin, anti-depressants, anti-psychotics, and sedating antihistamines),
    31. Allergic to the active ingredient of tapentadol or oxycodone or one or more of the excipients.
    32. Uncontrolled arterial hypertension.
    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)
    E.5.1.1Timepoint(s) of evaluation of this end point
    Subjects will be randomized to one of two treatment arms:
    Arm 1 (titrated from 50 mg up to max. 250 mg x 2/day tapentadol PR).
    or
    Arm 2 (titrated from 10 mg up to max. 50 mg x 2/day oxycodone CR).
    The treatment period is 4 weeks preceded by an up to 15 day's titration.
    Experimental mechanism based Pain Measures (EPMs) to be performed at visit: 3 and 6. A demonstration of the tests at visit 2.
    E.5.2Secondary end point(s)
    Change of pain severity from baseline to end of the 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.
    E.5.2.1Timepoint(s) of evaluation of this end point
    Timepoints for questionaires:
    PQAS, IGIC and PGAC; visit 3 and 6.
    BPI, WOMAC, self-paced walk test, stair climb test, DoloTest and PD-Q; visit 1, 3, 5 and 6.
    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 No
    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 Yes
    E.8.1.4Double blind No
    E.8.1.5Parallel group Yes
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) Yes
    E.8.2.2Placebo No
    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.8.5The 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: 48
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 12
    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 state60
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    None
    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 Decision2012-11-26
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2012-11-08
    P. End of Trial
    P.End of Trial StatusPrematurely Ended
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