Trial document





This trial has been registered retrospectively.
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  DRKS00004565

Trial Description

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Title

Efficacy and Safety of Migravent® vs. Placebo in Migraine Prevention: A Placebo Controlled, Randomized, Double-Blinded Parallel-Group Comparison for Superiority of Migravent®

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Trial Acronym

MIG.PRE.02

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URL of the Trial

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Brief Summary in Lay Language

New studies reveal that a mitochondrial dysfunction of energy metabolism in the neurons can be part of migraine pathophysiology. Many migraine patients have a deficit of the micronutrients riboflavin, magnesium and coenzyme in the blood, in cells, and also in the brain. A deficit of these nutrients could lead to migraine attacks. Riboflavin, magnesium and coenzyme Q10 play an important role in the production of energy in the mitochondria of cells. Based on these observations it seems plausible that a substitution of these micronutrients in migraine patients might be able to prevent or reduce migraine attacks. The commercially available food supplement Migravent® contains riboflavin, magnesium and coenzyme in high doses along with low-dose multi-vitamins for support of general health. The intended clinical trial is conducted to prove the efficacy of Migravent® in migraine prevention versus placebo in a randomized, placebo-controlled and double-blind design.

Patients with more than 3 migraine attacks per months pass through a run-in period without treatment for 1 month to determine baseline values. During that time they will fill out an online diary via the internet on a daily basis. Number, duration and severity of migraine attacks will be documented in the online diary as well as intake of acute pain medication and impairment of daily activities (home, work). Following this run-in phase of 30 days eligible patients will then be randomized to either Migravent® or placebo for a treatment period of 3 months. Again, patients will document the same migraine parameters in an online diary just as they did during the run-in phase. After the end of the 3 months treatment patients will visit the doctor for the final visit: they will fill out two questionnaires (HAD-S, HIT-6) as they did before randomization (treatment) and answer questions regarding subjective evaluations of efficacy and tolerability. In total, there will be 3 visits at the doctor´s office: recruitment and inclusion into run-in, randomisation into treatment arms (Migravent® or placebo) and final visit. To avoid bias neither the patient nor the doctor must know if Migravent® or placebo was administered (this is called double-blind). Migravent® is a nutritional supplement or food without known side effects.

An amendment was written to improve the quality of the primary endpoint. The primary endpoint "number of migraine attacks per 4 weeks in the last month of the 3 months-treatment" is replaced by the new primary endpoint "number of migraine days per 4 weeks in the last month of the 3 months-treatment". Due to this change the number of migraine attacks instead of the number of migraine days will be analysed as a secondary endpoint. There are no other changes.

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Brief Summary in Scientific Language

New studies reveal that a mitochondrial dysfunction of energy metabolism in the neurons can be part of migraine pathophysiology. The decrease of ATP as a consequence of the mitochondrial dysfunction could impair ion channel function and lead to migraine attacks. Magnesium, riboflavin and coenzyme Q10 play a central role in the mitochondrial energy metabolism. Magnesium plays an important role in various physiological processes which influence the pathophysiology of migraine. Magnesium is also needed as a co-factor for proper functioning of the enzyme ATP-synthase which produces ATP. Riboflavin is a precursor for the enzymes flavin-mononucleotide (FMN) and flavin-adenine-Dinucleotide (FAD). Both are essential components of complex I and complex II responsible for electron-transport in the mitochondrial membrane. Coenzyme Q10 is a vitamin-like compound which can be synthesized by the body from phenylalanine and tyrosine. Coenzyme Q10 is needed for all cellular processes requiring energy. Coenzyme Q10 level decrease with age. Coenzyme Q10 is an electron-carrier, transferring electrons from complex I / complex II to cytochrome C. Published reports show that some migraine patients have deficits of riboflavin, coenzyme Q10 and magnesium. Randomized and placebo-controlled clinical trials with riboflavin, magnesium and coenzyme Q10 as individual substances have demonstrated effectiveness in migraine prevention. The intended clinical trial is conducted to prove the efficacy of Migravent® in migraine prevention versus placebo in a randomized, placebo-controlled and double-blind design according to GCP /ICH und the guidelines of the EMA and IHS. Patients will be identified by screening of patient records or during visits to their neurologist for treatment of migraine.
Patients aged between 18 und 65 years with more than 3 migraine attacks per months during the last 3 months prior to study entry and who fulfill all inclusion and exclusion criteria will receive a screening number and pass through a run-in period without treatment for 1 month to determine prospective baseline values.
Eligible patients will then be randomized to either Migravent® or placebo for a treatment period of 3 months.
The observation period per subject will be a total of 4 months.

The investigational product (nutritional supplement) will be given to the patient after completion of the run-in period and must be taken every day for the complete duration of the 3 months treatment period. Treatment should start immediately after the run-in period.

Data collection and documentation for the assessment of the study endpoints will be performed

1) by the investigating physician using a paper based CRF at screening, after the run-in period and at the end of the treatment (end of trial). In addition the HIT-6 and HADS questionnaire will be filled out before randomization and after the end of the trial.
2) by the patient via internet access by filling out an online diary daily during the 1 month run-in and the 3 months treatment period.

Patients will be seen by the investigating doctor at the start of the trial (screening), after the run-in period (randomization and handout of the investigational product) and at the end of the study. Unscheduled visits in case of severe migraines or any other conditions that require a visit to the investigating doctor or any other doctor are initiated by the patient.

Migraine diagnosis will be confirmed at the start of the run-in phase.
All concomitant treatments are allowed except for medications, nutritional supplements and treatments used for migraine prevention. These are mainly beta-blockers (e.g. propranolol, bisoprolol, metoprolol), calcium-antagonists (e.g. flunarizine), antiepileptics (e.g. topiramate, valproate), antidepressanta (e.g. amitryptiline), supplements containing petasites (butterbur) or tanacetum (feverfew). Also magnesium, riboflavin or coenzyme Q10 in doses above 50 mg are not allowed. Non-medical / non-nutritional treatment for migraine prevention such as acupuncture or psychotherapy are also not allowed.
Pain medication to treat acute pain is allowed, not allowed is the daily (chronic) use of pain medication.

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Organizational Data

  •   DRKS00004565
  •   2013/01/18
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  •   no
  •   Approved
  •   FF 63/2012, Ethikkommission der Landesärztekammer Hessen
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Secondary IDs

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Health Condition or Problem studied

  •   migraine with and without aura
    G43
  •   G43 -  Migraine
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Interventions/Observational Groups

  •   Migravent®: 2 capsules with meals in the morning and 2 capsules in the evening.
    Substances: 400 mg riboflavin (Vitamin B2), 600 mg magnesium, 150 mg coenzyme Q10 per 4 capsules. In addition, Migravent® also contains various vitamins, minerals and trace minerals. Duration of Treatment: 3 months
  •   Placebo:2 capsules with meals in the morning and 2 capsules in the evening.
    Mode of Application: orally
    Duration of Treatment: 3 months
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Characteristics

  •   Interventional
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  •   Randomized controlled trial
  •   Blinded
  •   patient/subject, investigator/therapist, assessor, data analyst
  •   Placebo
  •   Prevention
  •   Parallel
  •   N/A
  •   N/A
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Primary Outcome

The primary endpoint is defined as the number of migraine days per 4 weeks in the last month of the 3 months-treatment.
The patients’ number of migraine days per 4 weeks will be determined during the last month of the 3-months-treatment period as well as during the 1 month run-in period (no treatment) for baseline adjustment.
Data collection and documentation for the assessment of the primary study endpoint will be performed by the patient via internet access by filling out an online diary daily during the 1 month run-in and the 3 months treatment period.

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Secondary Outcome

- Duration of migraine attacks
- Maximal intensity of migraine pain
- Number of migraine attacks
- Number of patients with at least 50% reduction in migraine attacks compared to the run-in period
- Number of patients with at least 50% reduction in migraine days compared to the run-in period
- Number of patients with a reduction in migraine attacks compared to the run-in period
- Number of patients with reduction in migraine days compared to the run-in period
- Number of days with acute pain medication
- Type and amount of pain medication
- Number of doctor visits due to migraine
- Number of days in hospital (overnight) due to migraine
- costs of migraine treatment
- Number of days unable to work (household / employment / school)
- Burden of disease measured by HIT-6
- Screening for depression or anxiety using HADS
- Subjective evaluation of efficacy by patient
- Subjective evaluation of tolerability by patient
- Adverse events
Data collection and documentation for the assessment of the secondary study endpoints will be performed

1) by the investigating physician using a paper based CRF at screening, after the run-in period and at the end of the treatment (end of trial). In addition the HIT-6 and HADS questionnaire will be filled out before randomization and after the end of the trial.
2) by the patient via internet access by filling out an online diary daily during the 1 month run-in and the 3 months treatment period.

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Countries of Recruitment

  •   Germany
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Locations of Recruitment

  • Medical Center 
  • University Medical Center 
  • Doctor's Practice 
  • University Medical Center 
  • Medical Center 
  • Doctor's Practice 
  • Doctor's Practice 
  • Doctor's Practice 
  • Doctor's Practice 
  • Doctor's Practice 
  • Doctor's Practice 
  • Medical Center 
  • Doctor's Practice 
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Recruitment

  •   Actual
  •   2012/10/12
  •   124
  •   Multicenter trial
  •   National
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Inclusion Criteria

  •   Both, male and female
  •   18   Years
  •   65   Years
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Additional Inclusion Criteria

1. Patients with migraine with and without aura diagnosed according to IHS-criteria ICHD-II 1.1 und 1.2.
2. Migraine was present and diagnosed at least one year before study entry.
3. The age at onset of migraine should be less than 50 years.
4. At least 3 migraine attacks per month in the last 3 months prior to study entry as well as in the run-in period. The duration of untreated attacks must not be less than 4 hours and not more than 72 hours.
5. The patient is able to distinguish between migraine and tension type headache.
6. The age of the patient is between 18 and 65 years.
7. The patient has internet access and is able to fill out the online diary.
8. Written informed consent.

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Exclusion Criteria

1. Less than 3 migraine attacks in the run-in period.
2. Use of migraine prevention (drugs, nutritional supplements or psychotherapy) during the last 3 months prior to study entry and throughout the study.
3. Use of antipsychotic or antidepressant medication during the last 3 months prior to study entry and throughout the study.
4. Chronic use of pain medication.
5. Failure to respond to more than 2 different prophylactic agents.
6. Patients resistant to all acute migraine drugs prescribed optimally.
7. Alcohol or drug abuse.
8. Patients with more than 10 days per month of migraine. A migraine day is a day with at least 4 hours of untreated headache and accompanying symptoms fulfilling the criteria of migraine.
9. Patients with more than 10 days per month of non-migraine headache.
10. History of hypersensitivity to the investigational nutritional supplement or to its ingredients.
11. Systemic, severe as well as history of uncontrolled chronic disease or a concurrent clinically significant illness, or medical condition, which in the investigator’s opinion, would contraindicate study participation or compliance with protocol mandated procedures.
12. Simultaneous participation in another clinical trial or participation in any clinical trial involving an investigational medicinal product or nutritional product within 30 days prior to written informed consent for this trial.
13. Patients unable to follow study procedures and unable to use an internet based diary.

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Addresses

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    • Weber & Weber GmbH & Co. KG
    • Herrschinger Strasse 33
    • 82266  Inning
    • Germany
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    •   08143-927-0
    •   08143-7084
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    • Weber & Weber GmbH & Co. KG
    • Mr.  Dr. rer. nat.  Ulrich  Danesch 
    • Herrschinger Str. 33
    • 82266  Inning / Ammersee
    • Germany
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    • Weber & Weber GmbH & Co. KG
    • Mr.  Dr.  Ulrich  Danesch 
    • Herrschinger Strasse 33
    • 82266  Inning
    • Germany
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Sources of Monetary or Material Support

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    • Weber & Weber GmbH & Co. KG
    • Herrschinger Str. 33
    • 82266  Inning
    • Germany
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Status

  •   Recruiting complete, follow-up continuing
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Trial Publications, Results and other Documents

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