Real-world Effectiveness and Tolerability of Triptans-Ditans-Gepants (TRIDIGEP)

Introduction Migraine is the third most prevalent disease and the leading reason of years lived with disability in the most productive years of the life. Migraine associated disability can be alleviated by acute and preventive treatment. The migraine landscape has changed in the recent year, with the approval of novel acute treatments, including oral Calcitonin gene-related peptide antagonists, the gepants (Rimegepant, Ubrogepant, Zavegepant) and 5-HT-1F antagonists, the Ditans (Lasmiditan). These have joined Triptans as acute "migraine-specific" drugs.

The reported efficacy of these drugs, assessed by 2-hours pain freedom, is between 25-40% in the case of triptans, 32-39% in the case of Lasmiditan, and 19-35% in the case of gepants. The Achilles tendon of some drugs is tolerability, which may decrease patients' adherence. In the randomized controlled trials (RCTs), the proportion of patients who reported treatment-emergent adverse events (TEAE) was between 2-25% in the case of triptans, 25-40% following Lasmiditan, and 13-17% after Rimegepant. In addition, adverse effects were drug-specific, though (but) luckily only resulted in treatment discontinuation in very few cases. However, due to restrictive eligibility criteria, the population represented in the RCT may differ from the general migraine population.

Aims This study aims to describe 1) the effectiveness of the acute treatments of migraine attacks in routine clinical practice, 2) the tolerability of the drugs, and 3) to explore potential response and tolerability predictors. The endpoints recommended by the International Headache Society will be employed, including: 1) Pain freedom; 2) Absence of the most bothersome symptom; 3) Sustained pain freedom; 4) Total freedom from migraine; 5) Headache relief; 6) Duration of attacks; 7) Time lost due to an attack; 8) Need of rescue medication. The study endpoints will be assessed at 2, 8 and 24 hours after the acute drug use.

This study will facilitate the collection of data from multiple attacks and many patients. The amount of collected data will permit the evaluation of additional outcomes and research questions, by using Big Data and Machine Learning approaches. These questions will include, among others, whether 1) the prompt use of the drug is associated with an increased probability of response; 2) the drug provides a consistent response within several treated attacks in patients; 3) there are any response or no-response predictors; 4) the tolerability of the drug is associated with individual or attack-related factors.

Hypotheses The study hypotheses are that the effectiveness and tolerability of the acute treatments of migraine could differ from the observed efficacy from the randomized clinical trials. The response and tolerability could be related to individual factors or the characteristics of the attack itself.

Study Design The TRIDIGEP study will be an open-label, multiple attack, prospective cohort study. The effectiveness and tolerability of the drugs will be prospectively described by the patients over multiple attacks.

Study Setting The study will be held in multiple headache centers and headache outpatient clinics from the world, including high-income and low-and-middle income countries. All consecutive patients evaluated in the participating sites will be considered for participating in the study. Patients will be informed about the study and invited to participate, if they accept, they will be screened for eligibility. Eligible patients will be trained in the use of the data collection instruments. They will be asked to record the study variables whenever they use the investigated drug products, for at least one attack, but ideally for every attack that they use the drug, ideally for at least five different attacks.

Data will be collected by the patients themselves, with a validated data collection instrument within a RedCap questionnaire. QR codes will be given to the patients to access three different questionnaires: the first one will include the informed consent form signature and the baseline demographic and clinical variables; the second will be for clinical characteristics of the acute migraine attack before the intake of the treatment and the 2-hours effectiveness of the employed drug; and the third one will include the same information in terms of effectiveness and tolerability of the acute drug but 8 and 24 hours after its use. This metodology will reflect how the different drugs are really used, so that factors that might be associated with a better or worse response will also be analyzed. Thus, the study will produce real-world data from many of them, and the benefits of the study will multiply, since data from several drugs will be collected in a standardized way, allowing comparative analyses.

Eligibility criteria Patients will be included if they 1) fulfill the criteria for migraine, according to the International Classification of Headache Disorders, 3rd version; 2) are treated with triptans, Lasmiditan or Gepants as acute therapies according to their responsible physician criteria under routine clinical practice criteria; 3) have a smartphone, tablet, or computer with an internet connection; 4) accept to participate and sign the informed consent form. Patients will be excluded if they 1) have a concomitant use of opioids, barbiturates, or ergot derivates; 2) have major cognitive or psychiatric disorders; 3) are unable to describe the result of the employed drug or have an insufficient proficiency of the local languages.

Variables The study will include demographic variables, prior medical history and clinical variables related with the treated migraine attacks. Demographic variables will include sex, date of birth, height, and weight. Clinical baseline variables will include the type of migraine, the number of headache and migraine days per month, on average, in the preceding three months, the presence of aura, the prior or current use of preventive medications, and the presence of comorbidities. The studied comorbidities will include arterial hypertension, diabetes, hyperlipidemia, smoking or former smoking habit, alcohol misuse; any disorder, including cardiovascular, pulmonary, neurological, neurosurgical, gastrointestinal, hepatic, kidney, otologic, endocrinologic, dermatologic, hematologic, allergy, immunological, oncological or psychiatric systems, including depression, anxiety, insomnia or others.

The information that will be collected related to the headache episode will include the presence of aura prior to the attack, the time when the headache started, and the moment when the drug was used, localization and quality of the pain, headache intensity, and the presence of associated symptoms, including photophobia, phonophobia, osmophobia, worsening by routine physical activity, nausea, vomiting, cranial autonomic symptoms, blurred vision or other symptoms. Patients will select the most bothersome symptom. The employed drug, including the dose and timing, will be assessed.

The clinical variables regarding effectiveness and tolerability will be assessed 2, 8 and 24 hours after drug intake. Effectiveness variables will include the headache intensity, and the presence of associated symptoms, using the same list, at the baseline and over the three time-points. The ability of functioning at the same time-points will be evaluated. Tolerability will be asked by an open question with a free-text response first, and afterwards, a list of possible AEs will be provided, including cutaneous rash, tiredness, gastrointestinal disturbances, constipation, somnolence, nausea, dizziness, vertigo, unsteadiness, sexual dysfunction, chest discomfort, weakness, reduced physical capacity, paresthesia, tingling, palpitations, bradycardia, tachycardia, blurred vision, and others. If patients report any of the listed Aes, a question regarding whether the symptom began after the drug intake or if it was present prior to the drug use will appear. The total duration of the headache, the time lost due to an attack, and the Global Impression of Change will be evaluated at 24 hours.

Data sources / measurements Patients will complete the study information in their smartphones, tablets or computers, using a QR code or a link that will redirect hem to the study questionnaires. RedCap will be used in the study. The questionnaires will be translated into the local languages.

Bias The Newcastle-Ottawa scale and the Risk of Bias in Non-randomized Studies of Interventions (ROBINS-I) criteria have been revised in the study design phase. Regarding patient selection, case definition will be based on the ICHD-3 criteria, cases will be representative of the entire migraine population, and they will act as their own controls, since the study will compare the situation before-after the drug intake.

The outcomes will be assessed with a record linkage through RedCap, and an independent statistician will assess them, blind to the participant's records. The follow-up will be long enough for the outcomes to occur, for 24-hours.

The study cohort will be followed-up adequately, with a complete follow-up. In case that patients are lost to follow-up, their characteristics will be described, and the reasons for patients lost will be provided.

None of the baseline variables will predict the intervention received.

Study size There is no sample size estimation, as we aim to enroll as many patients as possible. The aim is to surpass the sample sizes from the RCTS, which ranged between 200-1500 patients