Migraine, Headaches Clinical Trial
Official title:
Effect on Migraine Frequency of Combined Anti-oxidant Therapy: N-acetylcysteine, Vitamin E and Vitamin C (NEC): The MIGRANT Study
Migraine affects 15% of Western Australians and is a leading cause of suffering and disability in our community (1,2). Research suggests that inflammation of the brain's coverings (meninges) by nerve cell inflammation and the release of 'free radicals', is a cause of migraine. N-acetylcysteine, Vitamin E and Vitamin C are powerful anti-oxidants (free-radical scavengers) that reduce brain inflammation and nerve activity. It is therefore possible these anti-oxidants could reduce the number and severity of migraines. We will study 90 subjects to see if a combination of N-acetylcysteine 600 mg, Vitamin E 250 IU and vitamin C 500 mg (NEC) taken twice daily for 3 months, will reduce migraine attacks. This safe vitamin-based therapy has never been studied and if effective, will play an important role in migraine prevention.
Summary:
Migraine affects 15% of Western Australians and is a leading cause of suffering and
disability in our community. Research suggests that inflammation of the brain's coverings
(meninges) by nerve cell inflammation and the release of 'free radicals', is a cause of
migraine. N-acetylcysteine, Vitamin E and Vitamin C are powerful anti-oxidants (free-radical
scavengers) that reduce brain inflammation and nerve activity. It is therefore possible
these anti-oxidants could reduce the number and severity of migraines. We will study 90
subjects to see if a combination of N-acetylcysteine 600 mg, Vitamin E 250 IU and vitamin C
500 mg (NEC) taken twice daily for 3 months, will reduce migraine attacks. This safe
vitamin-based therapy has never been studied and if effective, will play an important role
in migraine prevention.
Because migraine is a complex neuro-vascular-inflammatory disorder with a 'cascade' of
steps, there are many potentially targets for drug prophylaxis. Research highlights the
importance brain neuro-inflammation mediated by Calcitonin Gene Related Peptide (CGRP) and
Substance P (SP), and oxygen and nitrogen free radical species (FRS) (eg. nitric oxide [NO])
in the pathogenesis of migraine. Increased levels of NO and CGRP were found in the jugular
venous blood migraineurs and NO produces cerebral vasodilation, which is a key step in
migraine generation. Furthermore, FRS activate the trigeminal-cervical nucleus (TCN) which
is the main centre of nociceptive (pain) sensitization in headaches—Sumatriptan blocks this
process accounting for some of its anti-migraine effect.
Anti-oxidants such as N-acetylcysteine (NAc), Vitamin C (ascorbic acid) (VitC) and Vitamin E
(alpha-tocopherol) (VitE) are potent FRS 'scavengers', which means they could be used to
prevent migraine. Two small non-randomised trials suggested that antioxidants reduced
migraine frequency and disability. Like sumatriptan, NAc reduces activation of the TCN by
NO, also neuro-inflammation in brain disorders such as Parkinson's disease. VitC and VitE
reduced NO levels in mice and VitC enhanced the neuro-inhibitory effects of gamma amino
butyric acid in the central nervous system—This mechanism could conceivably interrupt
'spreading cortical activation' which is the first step in the migraine cascade.
Migraineurs have an increased risk of developing an analogous neuro-inflammatory disorder,
Complex Regional Pain Syndrome (CRPS); increased plasma levels of SP, CGRP and FRS were
found in patients with these conditions. CRPS responds to treatment with NAc and VitC. A
meta-analysis found that combined (but not single-agent) anti-oxidant therapy (CAT) was safe
and effective in treating chronic pancreatitis, an inflammatory pain disorder similar to
both CRPS and migraine.
We previously proposed that migraine be considered a form of 'CRPS of the brain' which
therefore (like CRPS) may also respond to CAT. Literature review confirmed this theory has
not yet been explored. We will therefore test the hypothesis that twice-daily administration
of a combination of NAC 600 mg, VitE 250 IU and VitC 500 mg (NEC) for 12 weeks, will
significantly reduce migraine frequency. If proven effective, NEC will be an inexpensive,
accessible and safe treatment for managing the burden of migraine in the Western Australian
community
Experimental hypothesis Twice-daily administration of NEC (NAc 600 mg, VitE 250 IU and VitC
500 mg) for 12 weeks significantly reduces migraine frequency in patients who experience
two-to-eight migraines per month, compared with a placebo-control group.
Methods: Study design is based on guidelines for migraine clinical trials of the
International Headache Society (IHS) 2013. It will be a clinically-pragmatic,
proof-of-concept investigation.
Trial design: Prospective, randomised, double-blind, placebo-controlled, two parallel-group
trial.
Subjects: Males and females from 18 to 65 years of age.
Recruitment: Convenience sample of migraine patients attending general practice clinics,
neurology clinics linked to UNDA Sydney and pain clinics (Joondalup Health Campus); via
Headache Australia, Chronic Pain Australia, UNDA and Fremantle Hospital Research Foundation
websites, and newspaper advertising, as required.
NB: Subjects stabilised on one migraine prevention drug were not excluded from the study,
because cessation and washout of drugs would hinder recruitment and retention and does not
reflect 'real-life' clinical practice.
Power calculation The population for an adequately powered RCT was calculated from data of
similar studies in migraine prevention (30-35). It is estimated that 60% of subjects in the
active study group and 30% in the placebo-control group will report a 'positive outcome' (≥
30% reduction in headache frequency, from baseline). With 80% power and p<0.05, the study
population for this RCT is 84 subjects. An interim proof-of-concept (pilot) analysis will be
performed when 40 subjects (20 in each group) complete the study, based on guidelines for
pilot studies by Lancaster et al.
Number of subjects: 84 subjects in total, 42 in each study group. Active study group (n=42)
and placebo-control group (n=42).
Randomisation and blinding: Computer randomization of subjects will be in 'blocks' of 10, as
per IHS migraine trial guidelines. Subjects, researchers and data analysts will be blinded.
A pharmacist will dispense active (NEC) and sham trial drugs and maintain records.
Study duration: 16 weeks (112 days, or four months) total; four weeks baseline study phase
(for stabilization and baseline measurements); 12 weeks active study phase. Start: January
1, 2016. Finish: January 1, 2017.
Study logistics and flow:
- Ethics approval.
- Advertising.
- Serial recruitment of subjects.
- Informed consent obtained.
- Study enrolment interview with a researcher.
- Subjects provided with a paper headache diary which they must complete a minimum of
five days per week for 16 weeks of the study; should take no longer than 5 minutes per
day.
- Four weeks baseline study phase, baseline outcomes measures.
- After baseline phase, subjects stratified as having < 3 ≥ migraines per month, as per
IHS guidelines.
- Computer randomisation within these strata in 'blocks' of 10, as per IHS 2013.
- Randomised to active (NEC) or placebo-controlled (sham) study groups.
- They will need to take either verum or placebo tablet twice daily for 12 weeks.
- 12 week active study phase begins.
- Daily entries in headache diary.
- Control and compliance visits or phone contact every 4 weeks.
- Study termination face-to-face interview at the end of week 12.
- Collect diaries and left-over trial drugs.
- Data collated by blinded researcher.
- Statistical analysis performed by independent statistician.
- Data retained in a secure location for five years.
Data collection and analysis: Headache diary is based on; Headache diary-preventive
therapies, versions 4, IHS guidelines for controlled trials of drugs in migraine, 2011.
Headache diary must be completed for at least five days each week during the baseline and
active study phases. Study drugs must be consumed on at least five days each week during the
active study phase.
Intention-to-treat analysis: data from drop-outs and partial study completions will be
analysed and reported.
Statistical analysis: Analysis by an independent, blinded biostatistician from the UNDA
School of Medicine Health Research Institute, Fremantle WA, using SAS® version 9.2
statistical software (Cary NC, USA) and Excel spreadsheet 2007™ (Redmond WA, USA)
statistical packages. Analysis of outcomes will be performed on the intention-to-treat
population. Some post hoc analysis of data may be performed. Significance level: p<0.05;
confidence limits of 95%.
Data sets: Demographic, clinical, outcomes data. Descriptive data: Frequencies, percentages
(categorical data); means, standard deviations, confidence intervals (continuous data).
Comparative data analysis: Student's t test for continuous data; Chi square test for
categorical data; confidence intervals; linear or logistic regression.
Research team: MBBS honours student from UNDA; research nurse; research academics;
clinicians; statistician; pharmacist; secretarial support.
Equipment: Paper headache diary; NEC and sham drug capsules compounded by a pharmacy;
computers; consulting space; telephone and website access; secure data base.
References available on request.
;
Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Prevention