Triple Preventive Therapy with OnabotulinumtoxinA, Fremanezumab, and Atogepant in Treatment-Resistant Chronic Migraine: A 52-Week Pilot Case Series (TRIPLE Cohort)

A substantial proportion of patients with chronic migraine (CM) experience persistent disability despite advanced preventive monotherapies, including onabotulinumtoxinA (BoNT-A) and calcitonin gene-related peptide (CGRP)-targeted drugs. Evidence supporting combination strategies remains limited. We evaluated the long-term effectiveness and safety of triple preventive therapy with BoNT-A, fremanezumab, and atogepant in a real-world CM population with refractory disease. This ambispective, single-center case series included 14 adults with refractory CM treated sequentially with BoNT-A, fremanezumab, and add-on atogepant (60 mg daily). Patients were followed prospectively for 52 weeks during triple therapy. Primary outcomes were changes in monthly migraine days (MMDs) and monthly headache days (MHDs) through week 52. Secondary outcomes included acute medication use, responder rates, patient-reported outcomes, working status and descriptively reported adverse events and blood-pressure changes. The Patient Global Impression of Change (PGIC) evaluated overall patient-perceived clinical improvement. During triple therapy, MHDs declined from 24.4 ± 2.9 at baseline (stable BoNT-A plus fremanezumab treatment) to 19.0 ± 9.4 at week 52 (overall p = 0.029), with post hoc significance reached only at week 52 ( p = 0.020), indicating a delayed treatment effect to reach statistical significance. MMDs decreased progressively to 9.6 ± 5.3 at week 52 ( p < 0.001). The ≥ 50% responder rate increased from 28.6% at week 24 to 42.9% at week 52. Acute medication days declined from 12.1 ± 2.4 at baseline to 6.9 ± 2.7 at week 52 ( p < 0.001). PGIC scores were 6.5 ± 0.5 at week 52, indicating moderate-to-marked improvement. Working capacity improved substantially, with full-time activity increasing from 21.4% (3/14) at baseline to 71.4% (10/14) at week 52. No serious adverse events or treatment discontinuations were observed in this small cohort. In selected patients with treatment-resistant CM, triple preventive therapy was associated with delayed but clinically meaningful reductions in migraine burden and disability. No major tolerability issues were observed, although the small sample size precludes conclusions regarding safety. These findings support further evaluation of combination strategies in controlled studies.