E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Patients suffering from chronic migraine and medication overuse |
Patienten met chronische migraine en overgebruik van medicatie |
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E.1.1.1 | Medical 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. |
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E.1.1.2 | Therapeutic area | Diseases [C] - Nervous System Diseases [C10] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 14.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10066636 |
E.1.2 | Term | Chronic migraine |
E.1.2 | System Organ Class | 10029205 - Nervous system disorders |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main 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.
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E.2.2 | Secondary 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.
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
• Suffering from chronic migraine according to the ICHD-II criteria for chronic migraine as mentioned in paragraph 3.3.1.1, with medication overuse according to the ICHD-II criteria as mentioned in paragraph 3.3.1.2. |
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E.4 | Principal 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 Hydrocephalus-pump Denture with magnetic fixation Copper containing Intra-uterine Device History of surgery in which metal implants were implanted Weight over 160kg.
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E.5 End points |
E.5.1 | Primary 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. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
at 12 weeks after start of detoxification therapy (month 3)
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E.5.2 | Secondary 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.
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
All secondary endpoints will be assessed at timepoints 0, months 3, 6, 9 and 12. |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | Yes |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | No |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | Yes |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | Yes |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
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.8.5 | The trial involves multiple Member States | No |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.7 | Trial 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
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 3 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |