Real-world Effectiveness and Tolerability of Triptans-Ditans-Gepants (TRIDIGEP): an International Prospective Multicentric Cohort Study

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.