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    Summary
    EudraCT Number:2010-022556-23
    Sponsor's Protocol Code Number:KF6005/03
    National Competent Authority:Austria - BASG
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2011-06-29
    Trial results View 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 ConcernedAustria - BASG
    A.2EudraCT number2010-022556-23
    A.3Full title of the trial
    A randomized 4 week Phase IIa trial evaluating the efficacy, safety, and tolerability of GRT6005, a new centrally acting analgesic in subjects with moderate to severe pain due to osteoarthritis (OA) of the knee.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A 4-week trial evaluating the efficacy, safety, and tolerability of GRT6005, a new centrally acting analgesic, in subjects with moderate to severe pain due to osteoarthritis of the knee.

    A.4.1Sponsor's protocol code numberKF6005/03
    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 SponsorGrünenthal GmbH
    B.1.3.4CountryGermany
    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 organisationGrünenthal GmbH
    B.5.2Functional name of contact pointClinical Development Operations
    B.5.3 Address:
    B.5.3.1Street AddressZieglerstr. 6
    B.5.3.2Town/ cityAachen
    B.5.3.3Post code52078
    B.5.3.4CountryGermany
    B.5.4Telephone number+492415692509
    B.5.6E-mailclinical-trial@grunenthal.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 No
    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.3.1Product nameGRT6005 hard capsules (liquid filled with SEDDS_0708)
    D.3.2Product code GRT6005
    D.3.4Pharmaceutical form Capsule, hard
    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.3.9.1CAS number 863513-91-1
    D.3.9.2Current sponsor codeGRT6005, M010239FP, Indolyl-Spiroether pure
    D.3.9.3Other descriptive name6’-Fluoro-4’,9’-dihydro-N,N-dimethyl-4-phenyl-spiro[cyclohexane-1,1’(3’H)-pyrano[3,4-b]indol]-4-amin
    D.3.10 Strength
    D.3.10.1Concentration unit µg microgram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number25
    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 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 No
    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.3.1Product nameGRT6005 hard capsules (liquid filled with SEDDS_0708)
    D.3.2Product code GRT6005
    D.3.4Pharmaceutical form Capsule, hard
    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.3.9.1CAS number 863513-91-1
    D.3.9.2Current sponsor codeGRT6005, M010239FP, Indolyl-Spiroether pure
    D.3.9.3Other descriptive name6’-Fluoro-4’,9’-dihydro-N,N-dimethyl-4-phenyl-spiro[cyclohexane-1,1’(3’H)-pyrano[3,4-b]indol]-4-amin
    D.3.10 Strength
    D.3.10.1Concentration unit µg microgram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number50
    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: 3
    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 No
    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.3.1Product nameGRT6005 hard capsules (liquid filled with SEDDS_0708)
    D.3.2Product code GRT6005
    D.3.4Pharmaceutical form Capsule, hard
    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.3.9.1CAS number 863513-91-1
    D.3.9.2Current sponsor codeGRT6005, M010239FP, Indolyl-Spiroether pure
    D.3.9.3Other descriptive name6’-Fluoro-4’,9’-dihydro-N,N-dimethyl-4-phenyl-spiro[cyclohexane-1,1’(3’H)-pyrano[3,4-b]indol]-4-amin
    D.3.10 Strength
    D.3.10.1Concentration unit µg microgram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number200
    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 placeboCapsule, hard
    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
    Pain due to Osteoarthritis of the knee
    E.1.1.1Medical condition in easily understood language
    Pain due to degenerative arthritis in the knee (osteoarthritis)

    E.1.1.2Therapeutic area Diseases [C] - Musculoskeletal Diseases [C05]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 14.0
    E.1.2Level LLT
    E.1.2Classification code 10023476
    E.1.2Term Knee osteoarthritis
    E.1.2System Organ Class 10028395 - Musculoskeletal and connective tissue disorders
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 14.0
    E.1.2Level PT
    E.1.2Classification code 10031161
    E.1.2Term Osteoarthritis
    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 explore the analgesic efficacy of fixed doses of 75 µg, 200 µg, and 400 µg GRT6005 once daily compared to placebo in subjects with moderate to severe pain due to OA of the knee.
    E.2.2Secondary objectives of the trial
    To evaluate the safety and tolerability of fixed doses of 75 µg, 200 µg, and 400 µg GRT6005 once daily compared to placebo in subjects with moderate to severe pain due to OA of the knee.
    To investigate the relationship between exposure to GRT6005 and analgesic efficacy and tolerability.
    To describe multiple dose kinetics of GRT6005 over 4 weeks in subjects with pain due to OA of the knee.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Subjects must have signed an informed consent form.
    2. Male or female subjects aged 40 years to 75 years inclusive at the Enrollment Visit.
    3. Diagnosis of OA of the knee based on American College of Rheumatology criteria and functional capacity class of I-III. Pain must be present for at least 3 months.
    4. Subjects must be using medically acceptable and highly effective methods of birth control:
    For women of childbearing potential:
    A medically acceptable and highly effective method of birth control is defined as any form of contraception with a low failure rate defined as <1% per year. For example:
    - Hormonal contraceptives for at least 2 months prior to the Enrollment Visit and at least until 4 weeks after the Final Visit.
    - An intra-uterine device.
    Additional barrier contraception must be used by the partner for the duration of the trial, defined as from the time of the Enrollment Visit until 4 weeks after the Final Visit. Women of non-childbearing potential may be included if surgically sterile (i.e., after hysterectomy) or post-menopausal for at least 2 years.
    For men: Males have to use barrier contraception (condom) during sexual intercourse and not have sex with women who are pregnant or lactating from the first administration of IMP until 4 weeks after the Final Visit. The male subject has to take care that the female sexual partner uses at least 1 additional method of contraception with a low failure rate defined as <1% per year (e.g., oral contraceptives for at least 2 months prior to the Enrollment Visit) during this time frame. A double-barrier method should be supplemented by the use of spermicidal agents.
    5. Women of childbearing potential must have a negative urine β human chorionic gonadotropin (β-hCG) pregnancy test at the Enrollment Visit and at the Baseline Visit.
    6. Subjects must be on stable analgesic medications for their condition with regular intake for at least 3 months prior to the Enrollment Visit according to their medical history and must be dissatisfied with their current analgesic treatment in terms of efficacy and/or tolerability.
    7. A daily average pain intensity score ≥4 on the 11 point numeric rating scale (NRS) during the last 3 days prior to the Baseline Visit without intake of rescue medication, during which a subject completed at least 5 of 6 possible pain intensity assessments of these 3 days.
    E.4Principal exclusion criteria
    1. Concurrent participation in another trial, or within 30 days before the Enrollment Visit of this trial.
    2. Previous participation in this or other trials with GRT6005 (unless enrollment failure due to technical reason).
    3. Previous or current alcohol or drug abuse according to the investigator’s judgment, based on subject’s history, physical examination, or the result of the drug test at the Enrollment Visit or at the Baseline Visit.
    4. Previous or current opioid dependency, based on subject’s history, physical examination, or the result of the drug test at the Enrollment Visit or at the Baseline Visit.
    5. Female subjects who are breastfeeding.
    6. Known or suspected of not being able to comply with the protocol and with the use of the IMP.
    7. Any clinically significant disease that in the investigator's opinion may affect efficacy or safety assessments or may compromise the subject’s safety during trial participation, e.g., significant pulmonary, gastrointestinal, endocrine, metabolic, neurological, or psychiatric disorders.
    8. Employees of the investigator, trial site, or sponsor, with direct involvement in the proposed trial or other trials under the direction of that investigator, trial site, or sponsor, as well as family members of employees or the investigator.
    9. Subjects with impaired hepatic functionality/cellular integrity determined by bilirubin greater than 2.0 mg/dL and albumin lower than 2.8 g/dL or increased transaminases with alanine aminotransferase or aspartate aminotransferase greater than 3 times the upper limit of normal at the Enrollment Visit or at the Pre baseline Visit.
    10. History of chronic hepatitis B or C, or human immunodeficiency virus infection, or presence of acute hepatitis A, B, or C within the past 3 months.
    11. Subjects with impaired renal function. Creatinine clearance less than 60 mL/min at the Enrollment Visit or the Pre-baseline Visit (calculated from the Cockcroft-Gault formula).
    12. Any chronic gastrointestinal disease (e.g., celiac disease or colitis ulcerosa) or previous major abdominal surgery (e.g., Billroth procedure or enteroanastomosis) that might affect drug absorption or excretion.
    13. Significant cardiac disease (e.g., unstable angina pectoris, angina pectoris Canadian Cardiovascular Society Class III-IV, acute myocardial infarction within the last 3 months, cardiac insufficiency New York Heart Association Class III-IV).
    14. Presence of risk factors for Torsade de Pointes (e.g., heart failure, hypokalemia, bradycardia).
    15. Marked prolongation of QTc >450 ms at the Enrollment Visit or at the Pre baseline Visit.
    16. History of seizure disorder and/or epilepsy or any condition associated with a significant risk for seizure disorder or epilepsy at the Enrollment Visit at the discretion of the investigator.
    17. History or presence of malignancy, with the exception of curative treated subjects or subjects being in remission of cancer for at least 2 years and not requiring treatment.
    Trial specific:
    18. Surgery of any joint within 3 months of the Enrollment Visit or any scheduled surgery or painful procedure during the course of the trial.
    19. Clinically relevant history of hypersensitivity, allergy, or contraindications to any of the IMP’s excipients as well as to opioids or paracetamol.
    20. Presence of conditions other than pain due to OA that could contribute to pain or confound the assessment of self-evaluation of pain, for instance rheumatoid arthritis, psoriatic arthritis, gout, lupus, fibromyalgia, or significant skin conditions such as abscesses.
    21. Conditions that require treatment with prohibited medication (see Section “Concomitant treatments”).

    E.5 End points
    E.5.1Primary end point(s)
    Change from baseline in the pain intensity scores (on an 11 point NRS) during the last week of the 4 week Treatment Period. The pain intensity scores will be evaluated as the mean of the 2 average pain intensity assessments over the last 12 hours.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Complete last week of treatment

    E.5.2Secondary end point(s)
    a) Assessment of different responder definitions.
    b) Change from baseline in the pain intensity scores.
    c) Change from baseline in the pain intensity scores per week.
    d) Weekly mean of current pain intensity in the morning and in the evening.
    e) Western Ontario MacMaster Questionnaire
    f) Quality of Life Index
    g) Patient’s Global Impression of Change and Clinician’s Global Impression of Change.
    h) Leeds Sleep Evaluation Questionnaire.
    i) Assessment of rescue medication usage.
    j) Frequency of AEs and percentage of subjects discontinuing the trial due to AEs and drug-related AEs.
    k) Time to overall withdrawal and time to withdrawal for specific reasons.
    l) Evaluation of the plasma concentration of GRT6005
    m) Clinical Opioid Withdrawal Scale
    E.5.2.1Timepoint(s) of evaluation of this end point
    a) Visit 4, 5, 6, and at the Final Visit.
    b) during entire 4-week Treatment Period.
    c) Per treatment week and in the last 24 hours before Follow-up Visit.
    d) Per treatment week.
    e) Baseline Visit, Visit 5 and Visit 7.
    f) Visit 5 and Visit 7.
    g) Visit 5 and Visit 7.
    h) At Visit 5 and Visit 7.
    i) During the Treatment Period.
    j) Entire time.
    k) Entire time.
    l) Throughout the Treatment and Follow-up Periods.
    m) At Visit 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 Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence No
    E.6.9Dose response Yes
    E.6.10Pharmacogenetic Yes
    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 No
    E.8.1.4Double blind Yes
    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) No
    E.8.2.2Placebo Yes
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial4
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned5
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA24
    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
    last subject last visit
    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 months7
    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 months7
    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: 170
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 170
    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 state25
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 170
    F.4.2.2In the whole clinical trial 170
    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)
    Subjects will return to normal treatment after the end of the trial.
    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 Decision2011-07-28
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2011-06-07
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2011-12-15
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