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    EudraCT Number:2011-002768-25
    Sponsor's Protocol Code Number:191622-102
    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:2011-11-07
    Trial results View results
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    A. Protocol Information
    A.1Member State ConcernedDenmark - DHMA
    A.2EudraCT number2011-002768-25
    A.3Full title of the trial
    A Single Center, Double-blind, Randomized, Placebo-controlled, Parallel-group Study of the Efficacy and Safety of BOTOX® (Botulinum Toxin Type A) Purified Neurotoxin Complex as Treatment for Osteoarthritis Knee Pain
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Study of BOTOX® in the treatment of Osteoarthritis Knee Pain
    A.3.2Name or abbreviated title of the trial where available
    Study of BOTOX® in the treatment of Osteoarthritis Knee Pain
    A.4.1Sponsor's protocol code number191622-102
    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 AddressMarlow International, Parkway
    B.5.3.2Town/ cityMarlow, Buckinghamshire
    B.5.3.3Post codeSL6 1YL
    B.5.3.4CountryUnited Kingdom
    B.5.4Telephone number+441628494444
    B.5.5Fax number+441628494449
    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. name BOTOX®
    D. of the Marketing Authorisation holderAllergan Pharmaceuticals Ireland
    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.3.1Product nameBOTOX®
    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.3.9.1CAS number 93384-43-1
    D.3.9.2Current sponsor codeAGN 191622
    D.3.9.3Other descriptive nameBotox purified neurotoxin complex
    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 to Allergan Units
    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. cell therapy medicinal product No
    D. therapy medical product No
    D. Engineered Product No
    D. ATIMP (i.e. one involving a medical device) No
    D. 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
    Treatment of Osteoarthritis Knee Pain
    E.1.1.1Medical condition in easily understood language
    Treatment of Osteoarthritis Knee Pain
    E.1.1.2Therapeutic area Body processes [G] - Bones and nerves physological processes [G11]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 14.0
    E.1.2Level LLT
    E.1.2Classification code 10031165
    E.1.2Term Osteoarthritis 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
    The primary objective of this study is to evaluate the efficacy and safety of a single IA injection of BOTOX (200 U) compared with placebo as treatment for OA knee pain.
    E.2.2Secondary objectives of the trial
    Secondary objectives are to explore the efficacy of a single IA injection of BOTOX (200 U) compared with placebo on OA knee pain in patients with different pain phenotypes and/or different 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 and data protection consent has been obtained prior to initiating any study specific procedures.
    3. Primary idiopathic knee OA diagnosed in accordance with the ACR modified clinical classification criteria (Altman et al, 1986; Altman 1991) and verified radiologically as Kellgren-Lawrence grade I, II or III (Kellgren and Lawrence, 1957).
    4. For the study knee, the average daily worst pain score over the 14 days prior to day 1 (ie, days -14 to day -1) must be 4.0 to 9.0. The 14-day average score will be derived from daily worst pain scores recorded in a diary for the study knee.
    5. Stable knee pain in the study knee for ≥ 6 consecutive months prior to visit 1. No evidence of abnormal mechanical symptoms such as locking or catching of the study knee per medical history or physical examination.
    6. Body weight ≥ 40 kg and ≤ 150 kg with a body mass index (BMI) of 19 to ≤ 40 kg/m2 inclusive.
    7. For females of childbearing potential, a negative urine pregnancy test at screening, baseline, and on the day of the treatment (prior to the administration of the study medication) is required.
    8. 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.
    9. Ability to follow study instructions and likely to complete all required visits.
    10. Stable medical condition, in the investigator’s opinion.
    E.4Principal exclusion criteria
    1. Patient 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.
    2. History of or current evidence of rheumatoid arthritis as diagnosed by ACR criteria, or history of prior synovial fluid analysis of the study knee showing a white blood cell count ≥2000 mm3 that is indicative of a diagnosis other than OA.
    3. Presence of bursitis or tear of meniscus or ligament of the study knee, or history of significant knee injury to the study knee within 1 year of visit 1.
    4. History of surgery in the study knee within 24 weeks prior to visit 1, or already planned surgery of the study knee such as, arthroplasty, arthroscopy inspection, or repair of knee ligaments.
    5. Treatment with IA hyaluronic acid in the study knee within 24 weeks prior to visit 1.
    6. Treatment with IA corticosteroid in any joint or intramuscular corticosteroid administration within 12 weeks prior to visit 1.
    7. Concurrent chronic pain conditions such as back pain, hip pain (eg, disc herniation, peripheral nerve entrapment, multiple sclerosis), fibromyalgia that may interfere with assessment of the study knee. The study knee pain should be the predominant pain.
    8. History or current diagnosis of gout or pseudogout with knee involvement.
    9. History or current diagnosis of Reiter’s, Sjögren’s syndrome, psoriasis or systemic lupus erythematosus or other autoimmune diseases with joint involvement.
    10. Patients at a high risk of joint infection complication (eg, infection of local skin, soft tissue and joint in the study knee, indwelling urinary catheter) or have immunocompromised conditions (eg, known HIV or organ transplant).
    11. Evidence of abnormal coagulation status (eg, excessive tooth bleeding with brushing, abnormal bleeding time, partial thromboplastin time or prothrombin time) or patients with hemophilia or other blood diseases affecting coagulation (eg, aplastic anemia, leukemia, or under chemo-/radio-therapy).
    12. Patients continue to take excluded analgesic medications after visit 2.
    13. Patients with contraindications to the use of paracetamol (ie, rescue medication for this study).
    14. History of severe, progressive, or current unstable medical conditions other than OA such as renal, hepatic, gastrointestinal, neurological, endocrine, metabolic, degenerative bone disorders, respiratory, and/or psychiatric disorder as determined by medical history, physical examination and /or laboratory tests.
    15. History of severe cardiovascular diseases, stroke, recurrent seizures, frequent or severe allergic reactions to multiple medications.
    16. Electrocardiogram (ECG) abnormality at screening that in the opinion of the investigator could increase risk associated with participation in the study.
    17. Patients 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 at least 12 weeks prior to study start).
    18. Have a history of substance abuse or dependence within the past year, excluding nicotine and caffeine.
    19. Patient Health Questionnaire-9 (PHQ-9) score of >15 or a score of > 0 on item #9 of the PHQ-9 at week -4.
    20. Known allergy or sensitivity to the study medication(s) or its components.
    21. Females who are pregnant, nursing, or planning a pregnancy during the study period.
    22. Females of childbearing potential, not using a reliable means of contraception (See protocol Section for definition of acceptable methods of contraception).
    23. Current enrollment in an investigational drug or device study or participation in such a study within 30 days prior to entry into this study.
    24. Any medical or neurological condition that may put the patient 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.
    25. Previous treatment with botulinum toxin of any serotype for any reason or immunization to any botulinum toxin serotype.

    Too see full list of exclusion criteria see current Protocol.
    E.5 End points
    E.5.1Primary end point(s)
    Change from baseline:
    Daily worst pain score (11-point [0 to 10] NRS; 0 = no pain, 10 = worst pain possible) for the
    study knee
    E.5.1.1Timepoint(s) of evaluation of this end point
    4, 8 and 12 weeks post injection
    E.5.2Secondary end point(s)
    Change from baseline:
    • WOMAC Osteoarthritis Index NRS3.1:
    o WOMAC Total Index Score (0-240 scale)
    o WOMAC Pain Score (0-50 scale)
    o WOMAC Physical Function (difficulty performing daily activities) Score (0-170 scale)

    • Patient Global Impression of Change (Patient-GIC)
    The Patient-GIC is a questionnaire used by the patient to provide a global impression of change in their health status since enrollment, whether or not in the patient’s judgment a change is related to the study treatment. The Patient-GIC is useful in assessing whether the impact of the study treatment is meaningful enough to have value to the patient (Turk et al, 2003). A 7-point scale with +3 equaling very much improved and -3 equaling very much worse will be used for scoring purposes (Guy and Bonato, 1976). The Patient-GIC and other global impression questionnaires have a long history of use across a number of therapeutic areas and chronic pain indications (Farrar et al, 2001).
    Patient-GIC instructions: Since you enrolled into this study, how much have you changed? Please rate your total change whether or not, in your judgment, it is entirely due to the study treatment.
    Very much improved, Much improved, Minimally improved, No change, Minimally worse, Much worse, Very much worse
    E.5.2.1Timepoint(s) of evaluation of this end point
    1, 4, 8 and 12 weeks post injection
    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. 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 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
    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 months1
    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 months1
    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: 70
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 50
    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 state120
    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 previous treatment options
    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 Decision2011-11-10
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2011-10-24
    P. End of Trial
    P.End of Trial StatusCompleted
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