One-hundred-and-eighty subjects will be recruited for a placebo-controlled,
double-blinded study of idebenone (90 mg/day, 270 mg/day) versus placebo.
One-hundred-and-eighty subjects will be recruited based on past research and an expected
20% dropout rate. A dose of 90mg or 270 mg is based on large number of reports at study
initiation in Leber's hereditary optic neuropathy that demonstrated the safety of
900mg/day. Subjects are 18 to 65 years old, inclusive, who meet the International
Classification of Headache Disorder- III (ICHD-III) for episodic migraine with or without
aura, no over consumption of acute anti-migraine medication, no other prophylactic
medication (washout 3 months), no serious organic or psychiatric disease, who are
recommended to start prophylactic therapy (two to eight attacks per month). Written
informed consent is obtained. The process of patients through the trial phases follows
the CONSORT flow chart.
Idebenone and placebo were provided by Qilu Pharmaceutical Company Limited, China.
Placebo consisted of the same ingredients as verum-instead idebenone, they classify as
fit for human consumption in the China and without any known effect on migraine.
The design of this double-blind, randomized, placebo-controlled trial followed the IHS
Committee on Clinical Trials in Migraine guidelines, 8 current EU guidelines on Good
Clinical Practice, and the Declaration of Helsinki. It was approved by Neurology
Department, the Second Affiliated Hospital, School of Medicine, Zhejiang University. This
study is supported by the following funding sources: the Zhejiang Provincial Natural
Science Foundation of China (Grant No. LY19H090025, Grant No. LQ15H090003), the National
Natural Science Foundation of China (Grant No. 81101157). The study is also supported by
Qilu Pharmaceutical Company Limited, China (http://www.qilu-pharma.com); the use of
idebenone in migraine, is patent pending in the China. Dr. Kaiming Liu do not receive
honoraria from the sponsor of the study.
Exclusion criteria includes subjects who previously failed idebenone therapy for migraine
prophylaxis, those who previously discontinued idebenone due to adverse events, those who
are taking idebenone or had taken idebenone within 14 days prior to enrollment, and
subjects with continuous headaches. Subjects will be equally randomized to be treated
with 90 mg/day idebenone, 270 mg/day idebenone, or placebo for 3 months.
At the first visit, patients will receive placebo for a 1-month base-line. At the second
visit, they will be randomized to be treated with 90 mg/day idebenone, 270 mg/day
idebenone, or placebo for next 3 months if they have presented at least one migraine
attack.
The primary objective is to assess whether at least 1 dose of Idebenone is superior to
placebo in overall mean change from baseline of 4-week migraine headache days (MHD)
during double-blind treatment. Key secondary outcome variables will be change of migraine
attack frequency, migraine moderate/severe headache days, the proportion of subjects with
at least 50%, at least 75%, and 100% reduction in migraine days, mean severity of
migraine, acute treatment utilization, quality of life related to episodic migraine as
measured by the The Role Function Physical subscale in The Migraine-Specific Quality of
Life questionnaire (MSQ v2.1), migraine-related disability as measured by The Headache
Impact Test (HIT-6), Patient Global Impression of Severity (PGI-S) scores, and Migraine
Disability Assessment (MIDAS) scores from baseline of 4-week to the entire double-blind
treatment phase.
Responders for attack frequency (50% reduction) will be calculated and the
number-needed-to-treat (NNT) determined. Patients will be interviewed about adverse
events at each visit. Statistical analysis will be done on an intention-to-treat
population applying the last visit carried forward method. Mann-Whitney U test will be
used for differences between groups, 2 test for 22 contingency tables of responder rate,
general linear mixed model for evolution over time. Significance level is p<0.05, after
accounting for multiple comparisons. SPSS will be used.