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    Summary
    EudraCT Number:2014-001076-58
    Sponsor's Protocol Code Number:191622-145
    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:2014-11-19
    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 ConcernedDenmark - DHMA
    A.2EudraCT number2014-001076-58
    A.3Full title of the trial
    BOTOX® Efficacy and Safety in the Treatment of Knee Osteoarthritis
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    BOTOX® Efficacy and Safety in the Treatment of Knee Osteoarthritis
    A.4.1Sponsor's protocol code number191622-145
    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 SponsorAllergan Limited
    B.1.3.4CountryUnited Kingdom
    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 supportAllergan Limited
    B.4.2CountryUnited Kingdom
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationAllergan Limited
    B.5.2Functional name of contact pointAllergan Ltd. EU Regulatory Affairs
    B.5.3 Address:
    B.5.3.1Street Address1st Floor, Marlow International, The Parkway
    B.5.3.2Town/ cityMarlow, Buckinghamshire
    B.5.3.3Post codeSL7 1YL
    B.5.3.4CountryUnited Kingdom
    B.5.4Telephone number+441628494444
    B.5.5Fax number+441628494449
    B.5.6E-mailml-eu_reg_affairs@allergan.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 BOTOX®
    D.2.1.1.2Name of the Marketing Authorisation holderAllergan Pharmaceuticals Ireland
    D.2.1.2Country which granted the Marketing AuthorisationIreland
    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 nameBOTOX®
    D.3.2Product code 9060X
    D.3.4Pharmaceutical form Powder for solution for injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntraarticular use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNBotulinum Toxin Type A
    D.3.9.1CAS number 93384-43-1
    D.3.9.2Current sponsor codeAGN 191622
    D.3.9.4EV Substance CodeSUB13117MIG
    D.3.10 Strength
    D.3.10.1Concentration unit U unit(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 No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    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 Yes
    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 placeboPowder for solution for injection
    D.8.4Route of administration of the placeboIntraarticular use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Knee Osteoarthritis
    E.1.1.1Medical condition in easily understood language
    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 17.1
    E.1.2Level LLT
    E.1.2Classification code 10031165
    E.1.2Term Osteoarthritis 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 evaluate the efficacy and safety of a single IA injection of 400 U or 200 U BOTOX compared with placebo as treatment for knee OA symptoms
    E.2.2Secondary objectives of the trial
    To explore the efficacy of a single IA injection of BOTOX (400 U or 200 U) compared with placebo on knee synovial effusion neurotransmitter/biomarker concentration profiles.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Male or female, 40 to 75 years of age on the day of randomization (day 1).
    2. Written informed consent has been obtained.
    3. Written documentation has been obtained prior to initiating any study specific procedures in accordance with the relevant country and local privacy requirements, where applicable (e.g. Written Authorization for Use and Release of Health and Research Study Information (US sites) and written Data Protection consent (EU sites).
    4. Diagnosis of primary idiopathic OA in the study knee in accordance with the American College of Rheumatology (ACR) modified clinical classification criteria for ≥ 52 weeks prior to visit 1.
    5. Kellgren-Lawrence grade II or III as confirmed by x-ray obtained at visit 1 or ≤ 12 weeks prior to visit 1.
    6. Washout of all prohibited acute and chronic pain medications (eg, anti-inflammatory drugs and analgesics) other than protocol permitted rescue treatment or other medications/treatments allowed per protocol is
    completed at least 2 days prior to visit 2.
    7. The average daily pain score over the first 7 days after initiation of the baseline period must be 4.0 to 9.0. This score is specific for the study knee as derived from daily pain scores recorded by the subject in the e-diary.
    8. No evidence of abnormal mechanical symptoms such as locking or catching of the study knee per medical history or physical examination.
    9. If a subject has bilateral knee OA, the subject must be able to distinguish which knee is the predominant source of pain. This knee must be designated as the study knee.
    10. Body weight ≥ 60 kg and ≤ 150 kg inclusive.
    11. For females of childbearing potential, a negative urine pregnancy test at visits 1, 2, and 3 (prior to the administration of the study medication) is required.
    12. Must be ambulatory without assistive walking devices, able to perform usual daily activities, and agree to maintain the similar activity level throughout the course of the study.
    13. Subject’s global assessment of knee OA is ‘fair’, ‘poor’, or ‘very poor’ at visit 2.
    14. Ability to follow study instructions, likely to comply with the daily e-diary recording, and likely to complete all required visits.
    E.4Principal exclusion criteria
    1. Concurrent chronic pain conditions, or peripheral or central neuropathy that may affect sensation of the study knee area, including but not limited to back pain, hip pain, disc herniation, peripheral nerve entrapment, diabetic neuropathy, post-stroke pain, or fibromyalgia.
    2. painDETECT Questionnaire score ≥ 13 at visit 2.
    3. Subject diagnosed with any condition suggestive of a secondary cause of knee OA including but not limited to knee trauma, articular fracture, major dysplasias or congenital abnormality, acromegaly, ochronosis, hemochromatosis, Wilson’s disease, or primary osteochondromatosis.
    4. History of or current evidence of rheumatoid arthritis as diagnosed by American College of Rheumatology (ACR) criteria.
    5. Presence of bursitis, or tear of meniscus or ligament of the study knee, or history of significant injury or surgery to the study knee ≤ 52 weeks prior to visit 1.
    6. Surgery of the study knee, such as, arthroplasty, arthroscopy inspection, or repair of knee ligaments that is planned to occur during the study period.
    7. Treatment with IA hyaluronic acid in the study knee ≤ 24 weeks prior to visit 1.
    8. Treatment with IA corticosteroid in the study knee ≤ 12 weeks prior to visit 1.
    9. History or current diagnosis of gout or pseudogout with any joint involvement.
    10. History or current diagnosis of Reiter’s, Sjögren’s syndrome, psoriasis or systemic lupus erythematosus or other autoimmune diseases with any joint involvement.
    11. Evidence of skin infection or joint infection of the study knee.
    12. Evidence of abnormal coagulation status (eg, excessive tooth bleeding with brushing) or subjects with hemophilia or other blood diseases affecting coagulation (eg, aplastic anemia, leukemia), or under chemo-/radio-therapy.
    13. Use of prohibited medications or treatments for at least 2 days prior to initiating the baseline period or during the baseline period (which starts at visit 2 and ends at day -1)
    14. Subject has initiated or changed their established physiotherapy or occupational therapy program that is specific to the lower extremities ≤ 14 days prior to visit 3.
    15. Subjects using concomitant transcutaneous electrical nerve stimulation (TENS) or acupuncture to either lower extremity ≤ 14 days prior to visit 3.
    16. Subject does not record a minimum of 5 days’ worth of e-diary data for the first 7 days after initiation of the baseline period at visit 2.
    17. History of severe, progressive, or current unstable medical conditions other than OA.
    18. Subjects with an active malignancy of any type or a history of malignancy ≤ 5 years prior to visit 1, except for basal cell carcinoma of the skin that has been excised ≥ 12 weeks prior to visit 1.
    19. History of substance abuse or dependence ≤ 52 weeks prior to visit 1, excluding nicotine and caffeine.
    20. Subjects with moderately severe or severe depression as indicated by Patient Health Questionnaire-9 total score of ≥ 15 or a score of > 0 on item # 9 at visit 1.
    21. Subjects with severe anxiety as indicated by Generalized Anxiety Disorder score of ≥ 15 at visit 1.
    22. Subjects with clinically relevant level of catastrophizing defined as Pain Catastrophizing Scale score of ≥ 30 at visit 1.
    23. Known allergy or sensitivity to the study medication or its components.
    24. Females who are pregnant, nursing, or planning a pregnancy during the study period.
    25. Females of childbearing potential, not using a reliable means of contraception
    26. Current enrollment in an investigational drug or device study or participation in such a study ≤ 30 days prior to entry into this study (ie, visit 1) or prior enrollment in any study evaluating botulinum toxin of any serotype for any condition.
    27. Any medical or neurological condition that may put the subject at increased risk with exposure to BOTOX, including diagnosed myasthenia gravis, Eaton-Lambert syndrome, amyotrophic lateral sclerosis, concomitant use of aminoglycosides, or any other significant diseases that might interfere with neuromuscular function.
    28. Previous treatment with botulinum toxin of any serotype for any reason or immunization to any botulinum toxin serotype.
    29. Investigator site personnel directly affiliated with this study and/or their immediate families (defined as spouse, parent, child, or sibling, whether adopted or biologic).
    30. Subject has a condition or is in a situation which in the investigator's opinion, may put the subject at significant risk, may confound the study results, or may interfere significantly with the subject's participation in the study.
    E.5 End points
    E.5.1Primary end point(s)
    Change from baseline of the 7-day average of the daily pain score
    E.5.1.1Timepoint(s) of evaluation of this end point
    Week 8
    E.5.2Secondary end point(s)
    • WOMAC pain score
    • WOMAC physical function score
    • GIC
    • Daily worst pain score for the study knee
    E.5.2.1Timepoint(s) of evaluation of this end point
    The secondary efficacy WOMAC and GIC variables will be summarized for each visit week at which the variable is to be recorded.
    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 Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic No
    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 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 trial3
    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 concerned3
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA7
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Czech Republic
    Denmark
    United States
    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
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years1
    E.8.9.1In the Member State concerned months6
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years1
    E.8.9.2In all countries concerned by the trial months10
    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: 120
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 40
    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 state45
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 90
    F.4.2.2In the whole clinical trial 160
    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)
    Patients will return to the standard of care as appropriate for their condition.
    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 Decision2015-01-12
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2015-01-20
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2016-03-07
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
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