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    Summary
    EudraCT Number:2012-000062-38
    Sponsor's Protocol Code Number:191622-101
    National Competent Authority:Hungary - National Institute of Pharmacy
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2012-11-06
    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 ConcernedHungary - National Institute of Pharmacy
    A.2EudraCT number2012-000062-38
    A.3Full title of the trial
    BOTOX® Treatment in Pediatric Upper Limb Spasticity: Double-blind Study
    BOTOX® kezelés gyermekgyógyászati felső végtagi spaszticitásban: kettős vak vizsgálat
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Treatment of Spasticity in the upper limb in children
    Felső végtagi spaszticitás kezelése gyermekeknél
    A.4.1Sponsor's protocol code number191622-101
    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 Limited EU Regulatory Dept
    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.3.4Pharmaceutical form Powder for solution for injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntramuscular use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNBotulinum Toxin Type A
    D.3.9.2Current sponsor codeAGN 191622
    D.3.10 Strength
    D.3.10.1Concentration unit U unit(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number100
    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 placeboIntramuscular use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Upper Limb Spasticity.
    E.1.1.1Medical condition in easily understood language
    Upper Limb Spasticity.
    E.1.1.2Therapeutic area Diseases [C] - Musculoskeletal Diseases [C05]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 17.0
    E.1.2Level PT
    E.1.2Classification code 10028335
    E.1.2Term Muscle spasticity
    E.1.2System Organ Class 10029205 - Nervous system disorders
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 17.0
    E.1.2Level LLT
    E.1.2Classification code 10048970
    E.1.2Term Arm spasticity
    E.1.2System Organ Class 10029205 - Nervous system 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 evaluate the safety and efficacy of a single treatment of 2 doses (3 U/kg and 6 U/kg) of BOTOX with standardized occupational therapy (OT) in pediatric patients with upper limb spasticity.
    E.2.2Secondary objectives of the trial
    None
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    • Male or female, 2 to 16 years and 11 months of age (prior to 17th birthday) at the day 1 visit
    • Minimum weight of 10 kg at the screening and day 1 visits
    • Upper limb monoplegic, hemiplegic, or triplegic spasticity (spasticity confirmed by Hypertonia Assessment Tool [HAT]) with single-arm sparing (only 1 arm requiring botulinum toxin treatment for spasticity during the study) resulting from cerebral palsy, or post-stroke with the stroke onset prior to age 2 and at least 12 months prior to the day 1 visit
    • Patient’s spasticity meets at least one of the conditions below in the study limb at the screening and day 1 visits:
    o Elbow flexor tone of 2 or greater as measured by the MAS-B AND elbow flexor muscle contracture of no more than 30 degrees, and/or
    o Wrist flexor tone of 2 or greater with finger flexor tone of 1+ or greater as measured by the MAS-B
    AND at least neutral position for wrist with fingers at maximum extension
    • Gross Motor Function Classification System Expanded and Revised (GMFCS-E&R) level I to IV at the screening visit
    • Manual Ability Classification System (MACS) level I to IV at the screening visit
    • Patients who are on anti-spastic medications or muscle relaxants (eg, oral baclofen, tizanidine, dantrolene, scopolamine [oral or patch], vigabatrin, or benzodiazepine therapy) must be on a stable dose and regimen for at least 30 days prior to the day 1 visit
    • Patients who are on anti-epileptic medications must be on a stable dose and regimen for at least 30 days prior to the day 1 visit
    • Patients who are on an intrathecal baclofen pump must be on a continuous infusion at a stable dose and regimen (ie, not on bolus infusions) for at least 30 days prior to the day 1 visit
    • Written informed consent has been obtained from parent/legally authorized representative
    • Written minor assent has been obtained in accordance with local laws and institutional review board (IRB)/independent ethics committee (IEC) requirements
    • Written documentation has been obtained in accordance with the relevant country and local privacy requirements, where applicable (eg, Written Authorization for Use and Release of Health and Research Study Information for United States [US] sites and written Data Protection consent for European Union [EU] sites)
    • Negative urine pregnancy test at the screening and day 1 visits (for females of childbearing potential, defined as females post menarche)
    E.4Principal exclusion criteria
    - Any uncontrolled clinically significant medical condition other than the one under study
    - Any medical condition that may put the patient at increased risk with exposure to Botulinum Toxin Type A Purified Neurotoxin Complex, including diagnosed muscular dystrophy (eg, Duchenne’s muscular dystrophy), myasthenia gravis, Eaton-Lambert syndrome, amyotrophic lateral sclerosis, mitochondrial disease, or any other significant disease that might interfere with neuromuscular function
    - Fixed contracture of the principal muscle group (elbow or wrist) for the study limb
    - Uncontrolled epilepsy defined as more than 1 generalized seizure in any month within the 3 months prior to the day 1 visit or history of any of the following within 9 months prior to the day 1 visit:of prolonged seizures or repetitive seizure activity requiring administration of a rescue benzodiazepine (oral, rectal, etc) more than once a month, seizures lasting more than 10 minutes, status epilepticus, or epilepsy with autonomic involvement.
    - Patients with presence or history of any of the following within 12 months prior to the day 1 visit that may indicate a vulnerable respiratory state per the investigator’s clinical judgment: aspiration pneumonia, recurrent lower respiratory tract infections, uncontrolled asthma, or compromised respiratory function.
    - Patients with presence or history (within 12 months prior to the day 1 visit) of aspiration or a condition(s) that, in the investigator’s opinion, may put the patient at an increased risk for aspiration (eg, significant drooling, chronic dysphagia [difficulty swallowing] requiring changes in diet, or clinically significant gastroesophageal reflux disease)
    - Patients previously exposed to botulinum toxin therapy of any serotype who have a history of allergy or sensitivity to the toxin or its components or other significant adverse experiences that, in the investigator’s opinion, may put the patient at an unacceptable risk
    - Botulinum toxin therapy of any serotype for any condition within 6 months prior to the day 1 visit
    - History of treatment with phenol or alcohol block in the study limb within 12 months prior to the day 1 visit or planned treatment with phenol or alcohol block in any limb(s) during the study
    - History of or planned treatment during the study with selective dorsal rhizotomy or deep brain stimulation
    - Patient has had constraint-induced movement therapy within 2 months prior to the day 1 visit
    - History of surgical intervention of the study limb (except for tendon lengthening more than 12 months prior to the day 1 visit) or planned surgical intervention of any limb(s) during the study.
    - Previous casting within 6 months prior to the day 1 visit or splinting with a dynamic splint (eg, Dynasplint® or UltraFlex®) within 3 months prior to the day 1 visit for spasticity of the study limb or the affected lower limb(s), or planned casting or splinting with a dynamic splint (eg, Dynasplint or UltraFlex) for spasticity of the study limb or affected lower limb(s) during the study
    - Females who are pregnant, nursing, or planning a pregnancy during the study
    - Females of childbearing potential (defined as females post menarche) not using reliable means of contraception (see Section 4.5.1.1 for acceptable contraceptive methods)
    - Patients with a significant risk of suicide within the 12 months prior to screening, or since screening at the day 1 visit.
    E.5 End points
    E.5.1Primary end point(s)
    The primary efficacy endpoints will be the average grade change from baseline to weeks 4 and 6 in MAS-B of the principal muscle group. For US FDA only, the grade change from baseline in MAS-B of the principal muscle group and CGI by Physician are co-primary efficacy variables. Grade change from baseline in MAS-B of principal muscle group and CGI
    by Physician will be analyzed as co-primary endpoints for the average of weeks 4 and 6.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Baseline, weeks 4 and 6.
    E.5.2Secondary end point(s)
    The secondary efficacy variables of CGI by Physician and the MAS-B change from baseline for finger flexors will be evaluated at weeks 2, 4, 6, 8, and 12. The MAS-B change from baseline for finger flexors will be analyzed using the subgroup of patients with wrist identified as the principal muscle group. Functional goals (active and passive) using GAS
    by Physician will be evaluated separately relative to baseline at weeks 8 and 12, and MTS including the difference between slow (R2) and fast (R1) range of motion (R2 - R1) as well as respective change from baseline on the MTS of the principal muscle group at weeks 2, 4, 6, 8, and 12. Additionally changes from baseline for each R1 and R2 at each assessment point will be evaluated. In addition to each timepoint, the average of the weeks 4 and 6 for MAS-B change from baseline of the finger flexors and CGI by Physician will be analyzed.
    E.5.2.1Timepoint(s) of evaluation of this end point
    Baseline, weeks 2, 4, 6, 8, 12. Please refer to protocol for details.
    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) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    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 Yes
    E.8.4 The trial involves multiple sites in the Member State concerned No
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA26
    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
    Canada
    Germany
    Hungary
    India
    Italy
    Korea, Republic of
    Poland
    Russian Federation
    Spain
    Turkey
    United States
    E.8.7Trial has a data monitoring committee Yes
    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 years2
    E.8.9.1In the Member State concerned months9
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years3
    E.8.9.2In all countries concerned by the trial months3
    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 Yes
    F.1.1Number of subjects for this age range: 412
    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) Yes
    F.1.1.5.1Number of subjects for this age range: 206
    F.1.1.6Adolescents (12-17 years) Yes
    F.1.1.6.1Number of subjects for this age range: 206
    F.1.2Adults (18-64 years) No
    F.1.3Elderly (>=65 years) No
    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 Yes
    F.3.3.6.1Details of subjects incapable of giving consent
    The following may be enrolled but may not be able to give their written consent:
    - very young children
    - subjects with non-severe cognitive impairment related to their cerebral palsy (severe cognitive impairment is excluded by the protocol)
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state20
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 104
    F.4.2.2In the whole clinical trial 412
    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 who successfully complete this study without major protocol deviations will be given the option of enrolling in the open-label extension Study 191622-105 if they meet eligibility criteria. Otherwise patients would return to the standard of care treatment.
    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 Decision2013-01-03
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2012-12-18
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2017-07-06
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