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    The EU Clinical Trials Register currently displays   43974   clinical trials with a EudraCT protocol, of which   7312   are clinical trials conducted with subjects less than 18 years old.   The register also displays information on   18700   older paediatric trials (in scope of Article 45 of the Paediatric Regulation (EC) No 1901/2006).

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    EudraCT Number:2011-005124-18
    Sponsor's Protocol Code Number:LUMC-NEUR-0001
    National Competent Authority:Netherlands - Competent Authority
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2012-05-31
    Trial results
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    A. Protocol Information
    A.1Member State ConcernedNetherlands - Competent Authority
    A.2EudraCT number2011-005124-18
    A.3Full title of the trial
    Chronification and reversibility of migraine
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Chronification and reversibility of migraine
    A.3.2Name or abbreviated title of the trial where available
    A.4.1Sponsor's protocol code numberLUMC-NEUR-0001
    A.5.3WHO Universal Trial Reference Number (UTRN)U1111-1125-4826
    A.5.4Other Identifiers
    Name:Netherlands Trial RegisterNumber:12377
    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 SponsorLeiden University Medical Center
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportNederlandse Organisatie voor Wetenschappelijk Onderzoek (NWO)
    B.4.1Name of organisation providing supportAllergan Pharmaceuticals
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationLeiden University Medical Center
    B.5.2Functional name of contact pointD.A.Kies
    B.5.3 Address:
    B.5.3.1Street AddressAlbinusdreef 2
    B.5.3.2Town/ cityLeiden
    B.5.3.3Post code2300RC
    B.5.4Telephone number00310715262547
    B.5.5Fax number00310715248253
    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 Ltd
    D.2.1.2Country which granted the Marketing AuthorisationNetherlands
    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 name-
    D.3.2Product code -
    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 A
    D.3.9.1CAS number 93384-43-1
    D.3.9.2Current sponsor codeBotox
    D.3.9.3Other descriptive nameBOTULINUM TOXIN TYPE A
    D.3.9.4EV Substance CodeSUB13117MIG
    D.3.10 Strength
    D.3.10.1Concentration unit U/ml unit(s)/millilitre
    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 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 Yes
    D. medicinal product typeThe active constituent in BOTOX is a protein complex derived from Clostridium botulinum. The protein consists of type A neurotoxin and several other proteins.
    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 placeboSolution 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
    Patients suffering from chronic migraine and medication overuse
    Patienten met chronische migraine en overgebruik van medicatie
    E.1.1.1Medical condition in easily understood language
    Patients suffering from headache on more than 14 days per month of which at least 8 are migraine-days and overusing migraine and/or pain medication.
    Patienten met hoofdpijn op meer dan 14 dagen per maand waarvan minimaal 8 migraine-dagen en overgebruik van migraine- en/of pijn medicatie.
    E.1.1.2Therapeutic area Diseases [C] - Nervous System Diseases [C10]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 14.1
    E.1.2Level LLT
    E.1.2Classification code 10066636
    E.1.2Term Chronic migraine
    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
    1. We want to study the success rate of OAHM withdrawal in patients with chronic migraine related to support by a headache nurse, and onabotulinum toxin A injections during the withdrawal period, and the influence of comorbid depression.

    E.2.2Secondary objectives of the trial
    We want to study changes in ETVS (as measured by blink reflex) related to success rate of withdrawal and structural and functional changes in the brain.

    We want to study baseline (= before treatment) structural and functional brain differences in chronic migraineurs compared to control populations of episodic migraineurs, depressive patients, chronic pain patients and healthy controls.

    We want to study the reversibility of (regional) structural and functional changes in chronic migraineurs after withdrawal of OAHM.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    • Suffering from chronic migraine according to the ICHD-II criteria for chronic migraine as mentioned in paragraph, with medication overuse according to the ICHD-II criteria as mentioned in paragraph
    E.4Principal exclusion criteria
    • General exclusion criteria
    Age under 18 years
    Other neurological conditions that may in the opinion of the investigators may interfere with the trial. Any oncological or psychiatric disease, other than the specific types described in the inclusion criteria.
    Any cognitive disorders and/or behavioural problems which in the opinion of the clinician may interfere with the study.
    Current abuse of soft drugs or hard drugs or history of abuse of soft drugs or hard drugs in the past 12 months as defined in the DSM-IV criteria under 'Substance abuse' or 'Substance dependence'.(abuse of amphetamines, cocaine, heroin, cannabis)[104]
    Use of non-triptan or non-analgesic acute anti-headache medication (e.g. ergots, opioids, barbiturates).
    Pregnancy, planned pregnancy, current nursing. Additionally, all participants will be required to use adequate contraceptive methods.
    Inability to complete the (electronic) diary in a sensible and accurate manner
    Enrolment in other studies that in the opinion of the clinician may confound the results of this study

    • Btx-specific exclusion criteria
    Any motor neuron disorder.
    Hypersensitivity to any botulinum toxin preparation or to any of the components in the formulation
    Infection at the proposed injection site(s)
    (Suspected) clotting disorder; either of pathological or iatrogenic origin (e.g. caused by marcoumar, sintrom)

    • MRI-specific exclusion criteria
    Implanted pacemaker or implanted defibrillator-device
    Surgical clips in cerebral vasculature
    Metal debris in the eyes
    Non-removable hearing-aid
    Non-removable neurostimulator
    Denture with magnetic fixation
    Copper containing Intra-uterine Device
    History of surgery in which metal implants were implanted
    Weight over 160kg.
    E.5 End points
    E.5.1Primary end point(s)
    The primary outcome measure is the relative reduction in headache days per month, in a comparison of the last month of withdrawal (month 3) with the baseline period (month -1). A headache day is defined as a day on which there is at least one period of  4 hours of continuous headache. The relative reduction will be measured in the Btx and placebo groups and will be adjusted using multivariate analysis for depression scores at baseline and support by the headache nurse. As an alternative primary outcome measure, we will measure quality of life during the withdrawal trial. This will be measured by the Sumscore on the SF-36 questionnaire at timepoint 0, 1, 2 and 3.
    E.5.1.1Timepoint(s) of evaluation of this end point
    at 12 weeks after start of detoxification therapy (month 3)
    E.5.2Secondary end point(s)
    The differences between Btx and placebo groups will be assessed by measuring absolute and relative reduction in migraine and headache days on time points 3, 6, 9 and 12, the number of patients achieving a 50% or more decrease from baseline (month -1) in the frequency of migraine days and migraine episodes at time points 3 and 12 and absolute and relative reductions of HIT-6, CES-D and HADS-D scores at time points 3, 6, 9 and 12 and changes in these scores during the withdrawal trial. Also subjective satisfaction with both treatment and treatment outcome will be assessed.

    The difference between maximal versus minimal support by a headache nurse, responders (≥50% reduction in headache days) versus non-responders and depressive (HADS≥8) versus non-depressive chronic migraineurs will be assessed by measuring the absolute and relative reduction in migraine and headache days on time points 3, 6, 9 and 12, the number of patients achieving a 50% or more decrease from baseline (month -1) in the frequency of migraine days and migraine episodes at both time points and absolute and relative reductions of HIT-6, SF-36 CES-D and HADS-D scores at time points 3, 6, 9 and 12.

    Headache relapse rates at t=12 will be assessed and compared between Btx and placebo-treatment, minimal or maximal support by the headache nurse and depressive versus non-depressive groups.
    The change in reactiveness of the trigeminal blink reflex during the course of the trial will be assessed. Blink reflex will be tested at time points 0, 3 and 12.
    E.5.2.1Timepoint(s) of evaluation of this end point
    All secondary endpoints will be assessed at timepoints 0, months 3, 6, 9 and 12.
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis Yes
    E.6.3Therapy Yes
    E.6.4Safety No
    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) No
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) Yes
    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) Yes
    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 years3
    E.8.9.1In the Member State concerned months0
    E.8.9.1In the Member State concerned 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: 280
    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 Yes
    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 state280
    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)
    normal 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 Decision2012-05-31
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2012-07-12
    P. End of Trial
    P.End of Trial StatusCompleted
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