Nortriptyline Compared With Amitriptyline for Migraine Prevention at SQUH

This investigator-initiated, single-centre, randomized, blinded, active-comparator, parallel-group superiority trial will compare nortriptyline with amitriptyline for the preventive treatment of episodic migraine at Sultan Qaboos University Hospital, Muscat, Oman. Adults aged 18 to 65 years with migraine with or without aura will be screened. Eligibility requires a history consistent with episodic migraine and a prospective 28-day baseline showing 4 to 14 migraine days and fewer than 15 headache days, with at least 23 valid diary days. Ninety participants will be randomized in a 1:1 ratio. An independent statistician will generate an unstratified allocation sequence using randomly varying balanced permuted blocks. Allocation will be concealed through a pharmacy-controlled system. Participants, care providers, investigators, and outcome assessors will remain masked. Pharmacy personnel preparing the medicines and the statistician generating the allocation sequence will be unmasked. The medicines will be supplied in matching coded capsules containing 10 mg of the assigned medicine. The planned dose is 10 mg nightly during week 1, 20 mg during week 2, 30 mg during week 3, and 40 mg during week 4. The target from week 5 is 50 mg nightly when tolerated. Lower maintenance doses, temporary holds, reductions, or discontinuation are permitted for documented safety or tolerability reasons. Early subjective improvement alone will not determine a lower target during scheduled titration. Participants may decline escalation or stop treatment while continuing outcome follow-up. The final tolerated maintenance dose will be documented by week 6, with no routine escalation after day 42. Equal numerical doses are not assumed to be pharmacologically equivalent. The trial compares these specified treatment strategies. The randomized treatment period is 16 weeks. Randomization defines study day 1, and delayed treatment initiation or visits will not shift outcome windows. The primary endpoint period is days 85 to 112. Treatment will normally be tapered over the following two weeks, with a safety assessment at week 20. Appropriate ongoing migraine care will be arranged. The primary outcome is change from baseline in migraine days per 28 days during weeks 13 to 16. Secondary outcomes include the proportion achieving at least a 50% reduction in migraine days, changes in headache days and acute headache medication days, Headache Impact Test scores, Migraine Disability Assessment scores, treatment discontinuation because of adverse events, adverse events, serious adverse events, and body weight. Safety procedures include clinical assessment, electrocardiograms, relevant laboratory tests, medication interaction review, pregnancy testing where applicable, and psychiatric risk assessment. An independent safety physician will review emerging safety information. The sample size uses planning assumptions of a between-group difference of 2 migraine days per 28 days, a standard deviation of 3 days, 80% power, and a two-sided significance level of 0.05. Approximately 37 evaluable participants per group are required. Allowance for approximately 15% unavailable primary outcomes and rounding gives a target of 90 randomized participants. The primary analysis will follow the intention-to-treat principle and use analysis of covariance adjusted for baseline migraine days. The adjusted between-group difference will be reported with a 95% confidence interval. Missing outcomes will be addressed using prespecified multiple imputation and sensitivity analyses. Secondary analyses will be exploratory. A nonsignificant difference will not establish equivalence or noninferiority. Ethical approval will be sought from the Medical Research Ethics Committee, College of Medicine and Health Sciences, Sultan Qaboos University. Recruitment will begin only after ethics approval and other required institutional and regulatory permissions are obtained.