Nortriptyline Compared With Amitriptyline for Migraine Prevention at SQUH

NCT07856056 | Not Yet Recruiting Phase 4 DMC

• 1 other identifier: SQUH MIG TCA 01
• Study Type: interventional
• Target: 90
• Locations: 1 country
• Sites: 1

Brief Summary

This study will compare nortriptyline and amitriptyline for preventing migraine attacks in adults receiving care at Sultan Qaboos University Hospital in Oman. The researchers will assess whether the medicines differ in their effect on migraine frequency, side effects, and continued treatment use. Ninety adults with episodic migraine will be assigned by chance to receive either nortriptyline or amitriptyline, with 45 participants in each group. After completing a four-week baseline headache diary, participants will take the assigned medicine each evening for 16 weeks. Treatment will start at 10 mg nightly and increase gradually toward 50 mg nightly when tolerated. Lower doses will be permitted for safety or tolerability reasons. Participants and the clinical assessment team will not know which medicine has been assigned. The main outcome will be the change in migraine days during the final four weeks of treatment compared with baseline. Other outcomes will include headache days, use of medicines for acute headache, headache impact, migraine-related disability, adverse events, and stopping treatment because of adverse events. Treatment will usually be tapered over two weeks, with a final safety assessment at week 20 after randomization. Participation will last approximately 24 weeks, including the baseline period. Appropriate acute migraine treatment will remain available throughout the study.

Conditions

Migraine

Keywords

Episodic migraine; Migraine prevention; Nortriptyline; Amitriptyline

Outcome Measures

Primary Outcomes (1)

• Change From Baseline in Migraine Days per 28 Days During Weeks 13 to 16

  Migraine days will be measured using a daily diary. A qualifying day contains headache lasting at least 30 minutes with migraine or probable migraine features, or qualifying headache accompanying previously confirmed typical aura. Headache successfully treated with a migraine-specific acute medicine also qualifies, including when shorter than 30 minutes. Aura without headache is excluded. Successful acute treatment means improvement within two hours from moderate or severe pain to mild or no pain, or from mild pain to no pain. Multiple qualifying attacks on one day count once. For periods with at least 23 valid days, counts will be standardized to 28 days. Change is the count during days 85 to 112 minus the prospective baseline count. Negative values indicate improvement.

  Baseline, the 28 days before randomization, and weeks 13 to 16 after randomization, days 85 to 112

Secondary Outcomes (6)

• Percentage of Participants With at Least a 50% Reduction in Migraine Days

  Baseline, the 28 days before randomization, and weeks 13 to 16 after randomization

• Change From Baseline in Acute Headache Medication Days per 28 Days

  Baseline, the 28 days before randomization, and weeks 13 to 16 after randomization

• Change From Baseline in Headache Impact Test Total Score

  Baseline and week 16 after randomization

• Change From Baseline in Migraine Disability Assessment Total Score

  Baseline and week 16 after randomization

• Percentage of Participants Discontinuing Assigned Treatment Because of an Adverse Event

  From the first study dose through day 112 after randomization

Study Arms (2)

Nortriptyline

EXPERIMENTAL

Participants will receive oral nortriptyline each evening for 16 weeks. The planned dose is 10 mg nightly in week 1, 20 mg in week 2, 30 mg in week 3, and 40 mg in week 4, followed by a target of 50 mg nightly from week 5 when tolerated. Lower doses and treatment interruptions are permitted for safety or tolerability. The final maintenance dose will be documented by week 6, with no routine escalation after day 42. Treatment will normally be tapered after week 16, with safety follow-up at week 20.

Drug: Nortriptyline

Amitriptyline

ACTIVE COMPARATOR

Participants will receive oral amitriptyline each evening for 16 weeks. The planned dose is 10 mg nightly in week 1, 20 mg in week 2, 30 mg in week 3, and 40 mg in week 4, followed by a target of 50 mg nightly from week 5 when tolerated. Lower doses and treatment interruptions are permitted for safety or tolerability. The final maintenance dose will be documented by week 6, with no routine escalation after day 42. Treatment will normally be tapered after week 16, with safety follow-up at week 20.

Drug: Amitriptyline

Interventions

Nortriptyline DRUG

Oral nortriptyline supplied in matching coded 10 mg capsules. Participants will take one to five capsules nightly according to the prescribed schedule, starting at 10 mg and increasing no more frequently than weekly toward 50 mg when tolerated. Dose adjustments will follow prespecified safety and tolerability rules. The randomized treatment period is 16 weeks, normally followed by an individualized taper over approximately two weeks.

Nortriptyline

Amitriptyline DRUG

Oral amitriptyline supplied in matching coded 10 mg capsules. Participants will take one to five capsules nightly according to the prescribed schedule, starting at 10 mg and increasing no more frequently than weekly toward 50 mg when tolerated. Dose adjustments will follow prespecified safety and tolerability rules. The randomized treatment period is 16 weeks, normally followed by an individualized taper over approximately two weeks.

Amitriptyline

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Age 18 to 65 years at consent, of any sex or nationality, receiving care at Sultan Qaboos University Hospital and able to attend the required visits.
• Migraine with or without aura diagnosed according to the International Classification of Headache Disorders, third edition, present for at least 12 months, with onset before age 50 years.
• A history consistent with episodic migraine during the preceding three months and a prospective baseline showing 4.0 to 14.0 migraine days inclusive and fewer than 15 headache days per 28 days.
• A clinical indication for preventive therapy agreed by the treating clinician and participant.
• At least 23 valid diary days during the prospective 28-day baseline. Frequency thresholds will be assessed using standardized 28-day counts without rounding.
• Ability to provide informed consent and complete an Arabic or English diary independently or with approved assistance that records the participant's own responses.
• For participants who could become pregnant, a negative pregnancy test and agreement to an effective contraceptive approach or consistent abstinence where this reflects usual practice, from consent until 30 days after the last study dose.

You may not qualify if:

• Chronic migraine, another predominant headache disorder, suspected secondary headache, a trigeminal autonomic cephalalgia, or inability to distinguish migraine from other recurrent head pain. Hemiplegic migraine and migraine with brainstem aura are excluded. Typical visual or sensory aura is eligible.
• Medication overuse headache or sustained acute medication use at overuse thresholds during the preceding three months. Use on 10 or more days per month of triptans, ergots, opioids, combination analgesics, or mixed acute drug classes, or on 15 or more days per month of simple analgesics or nonsteroidal anti-inflammatory drugs, will exclude participation. Baseline diary use meeting these thresholds will also exclude participation.
• Previous clear treatment failure after an adequate course of either trial medicine, or previous clinically important intolerance, allergy, or contraindication to either medicine or its excipients. An adequate course is at least eight weeks at a tolerated dose of at least 25 mg nightly with insufficient benefit. Brief previous exposure without established failure is permissible if completed at least three months before screening and recorded.
• Current migraine preventive medication or another treatment with substantial preventive activity that cannot safely be stopped. Oral preventive medicines must have been discontinued for at least four weeks and at least five elimination half-lives, whichever is longer, before baseline. OnabotulinumtoxinA or peripheral nerve blocks for prevention within four months, or a calcitonin gene-related peptide monoclonal antibody within six months or five half-lives, whichever is longer, will exclude participation. Preventive gepants follow the oral preventive washout rule. Effective treatment will not be withdrawn solely to enable enrollment when clinically inappropriate.
• Current use of another antidepressant, a monoamine oxidase inhibitor, or a clinically important interacting medicine that cannot safely be avoided. All prescribed, nonprescribed, and herbal products will undergo pharmacist review. A prior monoamine oxidase inhibitor requires at least a 14-day interval, with any longer product-specific interval respected. Recent fluoxetine or another long-acting inhibitor requires an individualized documented washout. Psychiatric treatment will not be withdrawn simply to meet trial eligibility.
• Previous myocardial infarction with ongoing risk, clinically significant ischemic or structural heart disease, heart failure, clinically important arrhythmia, unexplained syncope, congenital long QT syndrome, Brugada syndrome, or a family history suggesting an inherited arrhythmia without satisfactory specialist assessment.
• Baseline corrected QT interval using Fridericia's formula above 450 milliseconds in men or 470 milliseconds in women, QRS duration of 120 milliseconds or greater, any degree of atrioventricular block including PR above 200 milliseconds, or another clinically significant electrocardiographic abnormality. A borderline or technically inadequate trace may be repeated and reviewed before eligibility is determined.
• Uncontrolled epilepsy, previous serious drug-related seizure, untreated narrow-angle glaucoma, clinically important urinary retention, paralytic ileus, untreated hyperthyroidism, or a comparable condition increasing tricyclic treatment risk.
• Bipolar I or II disorder, previous antidepressant-induced mania or hypomania, current psychosis, current suicidal intent or plan, a suicide attempt within the preceding year, or another psychiatric condition requiring treatment incompatible with the protocol. Stable anxiety or mild depressive symptoms alone will not exclude participation.
• Current moderate or severe substance use disorder likely to affect safety or reliable participation.
• Pregnancy, breastfeeding, planned pregnancy during participation, or inability to follow the agreed pregnancy prevention arrangements.
• Participation in another interventional trial within the preceding 30 days or five investigational drug half-lives, whichever is longer.
• A condition, planned procedure, or practical limitation preventing informed consent, reliable outcome assessment, or safe completion, with a specific reason documented by the investigator.

Sponsors & Collaborators

• Sultan Qaboos University: lead

Study Sites (1)

Sultan Qaboos University Hospital, University Medical City

Muscat, Oman

Location

Related Publications (3)

• Roghani M, Ghaedi G, Iranzadeh S, Golezar MH, Afshinmajd S. Efficacy and safety of venlafaxine versus nortriptyline for the preventive treatment of migraine: A double-blind randomized clinical trial. Clin Neurol Neurosurg. 2024 Aug;243:108400. doi: 10.1016/j.clineuro.2024.108400. Epub 2024 Jun 17.

  PMID: 38901375 BACKGROUND

• Goncalves AL, Martini Ferreira A, Ribeiro RT, Zukerman E, Cipolla-Neto J, Peres MF. Randomised clinical trial comparing melatonin 3 mg, amitriptyline 25 mg and placebo for migraine prevention. J Neurol Neurosurg Psychiatry. 2016 Oct;87(10):1127-32. doi: 10.1136/jnnp-2016-313458. Epub 2016 May 10.

  PMID: 27165014 BACKGROUND

• Diener HC, Tassorelli C, Dodick DW, Silberstein SD, Lipton RB, Ashina M, Becker WJ, Ferrari MD, Goadsby PJ, Pozo-Rosich P, Wang SJ, Houle TT, Hoek TCVD, Martinelli D, Terwindt GM; International Headache Society Clinical Trials Committee. Guidelines of the International Headache Society for controlled trials of preventive treatment of migraine attacks in episodic migraine in adults. Cephalalgia. 2020 Sep;40(10):1026-1044. doi: 10.1177/0333102420941839. Epub 2020 Jul 28.

  PMID: 32722936 BACKGROUND

MeSH Terms

Conditions

Migraine Disorders

Interventions

Nortriptyline; Amitriptyline

Condition Hierarchy (Ancestors)

Headache Disorders, Primary; Headache Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases

Intervention Hierarchy (Ancestors)

Dibenzocycloheptenes; Benzocycloheptenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Polycyclic Compounds

Central Study Contacts

Mohammed Al.Alawi, MD, PhD, MBA, MRCPsych UK

CONTACT

96824141511; m.alalawi2@squ.edu.om

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: PARTICIPANT
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Assistant Professor

Study Record Dates

• First Submitted: September 27, 2026
• First Posted: October 2, 2026
• Study Start (Estimated): May 1, 2027
• Primary Completion (Estimated): May 1, 2030
• Study Completion (Estimated): December 1, 2030
• Last Updated: October 2, 2026

Record last verified: 2026-09

Locations

OM (1)