Trial Report Ubrogepant for the treatment of migraine prodromal symptoms: an exploratory analysis from the randomized phase 3 PRODROME trial, 2025, Goadsby et al

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Ubrogepant for the treatment of migraine prodromal symptoms: an exploratory analysis from the randomized phase 3 PRODROME trial

Peter J. Goadsby, Jessica Ailani, David W. Dodick, Amaal J. Starling, Chengcheng Liu, Yingyi Liu, Sung Yun Yu, Jonathan H. Smith, Elimor Brand-Schieber & Joel M. Trugman

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Abstract
PRODROME was a phase 3, placebo-controlled, double-blind crossover trial evaluating whether ubrogepant 100 mg, a calcitonin gene-related peptide receptor antagonist, dosed during the premonitory (prodromal) phase of migraine, prevented development of headache and resolved prodromal symptoms. Qualifying prodromal events were defined as attacks with symptoms in which the participant was confident headache would follow within 1–6 h. Of 1,087 screened participants, 477 formed the efficacy analysis population.

Outcomes were collected across 48 h showing, for example, at 2 h post-dose, absence of photophobia in 19.5% and 12.5% of ubrogepant- and placebo-treated events, respectively (odds ratio (OR) = 1.72 (95% confidence interval (CI) = 1.13–2.61)); at 3 h post-dose, absence of fatigue occurred in 27.3% and 16.8% (OR = 1.85 (95% CI = 1.17–2.92)) and absence of neck pain in 28.9% and 15.9% (OR = 2.04 (95% CI = 1.25–3.32)) of events; at 4 h post-dose, absence of phonophobia in 50.7% and 35.8% (OR = 1.97 (95% CI = 1.38–2.80)) of events; and at 24 h post-dose, absence of dizziness in 88.5% and 82.3% (OR = 1.82 (95% CI = 1.00–3.30)) of events.

At 1 h and 6 h post-dose, respectively, absence of difficulty concentrating occurred in 8.7% and 2.1% (OR = 4.26 (95% CI = 1.17–15.54)) and absence of difficulty thinking occurred in 56.9% and 41.8% (OR = 2.05 (95% CI = 1.14–3.71)) of events.

Treatment with ubrogepant during the prodromal phase may ameliorate common prodromal symptoms, with improvements possibly as early as 1 h post-dose.

Link | PDF (Nature Medicine) [Open Access]
 
Nature News: 'Migraine drug is first to tackle debilitating early symptoms' [Paywall]

"Scientists have shown that a drug approved to treat migraine headaches can also alleviate debilitating non-headache symptoms, such as fatigue, brain fog and blinding light sensitivity, that occur as the migraine is starting.

The drug — called ubrogepant — is already known to stop the onset of a full-blown migraine attack in some people if they take it when the headache begins. But a phase III clinical trial, described in Nature Medicine on 12 May1, shows that it can also tackle the ‘prodrome’ symptoms that arrive hours or even days earlier."

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"But the “effect sizes were small” and never more than 15 percentage points compared with the placebo, points out Gregory Dussor, a neuroscientist and migraine specialist at the University of Texas at Dallas. For example, 27% of participants who took ubrogepant reported an absence of fatigue, compared with 17% who took the placebo. Dussor suggests this modest improvement is because the class of drugs to which ubrogepant belongs is a “life-changing therapeutic” for a minority of people — perhaps only one in five, according to some studies. It makes little difference to others, so its effect for that minority “gets diluted in the data”."
 
I have a monthly injection of Ajovy (similar type of therapy) and it is remarkable the difference. Not only to my migraine frequency and severity but also to my balance, pain, fatigue etc. These types of interventions are life changing. They move migraine management from coping to prevention. I refer patients over to the Walton Centre weekly.

Please do look into monoclonal antibody treatment for migraine if you have severe headaches/migraine. GPs can refer to tertiary headache clinics.
 
NHS GP's are also beginning to prescribe gepants now too (under direction from specialist clinics). Atogepant taken preventatively seems to be roughly as effective as the mabs and doesn't have the concern over long washout.
 
How feasible is blinding with this drug? I can’t find any data on it.

The outcomes were subjective, and if the participants were able to tell if they got the drug or placebo, it might influence their reporting.
 
Utsikt said:
How feasible is blinding with this drug? I can’t find any data on it.

The outcomes were subjective, and if the participants were able to tell if they got the drug or placebo, it might influence their reporting
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According to this pub of 2022

Rimegepant, Ubrogepant, and Lasmiditan in the Acute Treatment of Migraine Examining the Benefit-Risk Profile Using Number Needed to Treat/Harm ​

All 3 treatments demonstrated efficacy and safety in randomized, double-blind, placebo, controlled trials (RCTs).13,18–26
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I haven’t examined the references, the references to ubregepant are:

  • 18. ClinicalTrials.gov. Efficacy, Safety, and Tolerability Study of Oral Ubrogepant in the Acute Treatment of Migraine (ACHIEVE I). NCT02828020. 2019. Available at: https://clinicaltrials.gov/ct2/show/NCT02828020. Accessed August 6, 2020.
  • 19.https://clinicaltrials.gov/ct2/show/NCT02867709 ClinicalTrials.gov. Efficacy, Safety, and Tolerability of Oral Ubrogepant in the Acute Treatment of Migraine (ACHIEVE II). NCT02867709. 2019. Available at: . Accessed August 6, 2020.
  • 23. Dodick D, Lipton R, Ailani J, et al. Ubrogepant for the treatment of migraine. N Engl J Med. 2019;381:2230–2241. [DOI] [PubMed] [Google Scholar]
  • 26. Lipton R, Dodick D, Ailani J, et al. Effect of ubrogepant vs placebo on pain and the most bothersome associated symptom in the acute treatment of migraine the ACHIEVE II Randomized Clinical Trial. JAMA. 2019;322:1887–1898. [DOI] [PMC free article] [PubMed] [Google Scholar]
 
Jonathan Edwards said:
I would not expect that necessarily to be a problem.
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Could you elaborate on why not? It seems important to know if a drug might have side effects that could break blinding.

For example, might nausea clue people in to whether they received the drug?
Treatment-related TEAEs were identified in 42 of 462 (9%) of placebo-treated events and 60 of 456 (13%) ubrogepant 100 mg-treated events. As previously reported20, there were no adverse events (AEs) leading to study discontinuation and no serious AEs. The most common AEs (≥2%) after placebo and ubrogepant administration were nausea (3% versus 5%), fatigue (2% versus 3%), dizziness (3% versus 2%) and somnolence (1% versus 2%).
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I am also a very long term chronic migraine sufferer of over 40 years and I now take Atogepant but have had endless problems in tolerating it even at the lowest dose of
10 mg.

I know that the gepants are metabolised by CYP3A4 and are a strong inhibitor of this pathway but unfortunately so is Prednisolone which I have to take as I am steroid dependant so I believe that this might be the issue even when taken 3 hours apart.

After much trial and error I don’t get strong side effects if I take the Atogepant after my evening meal. It is the only drug that has made a big difference to all the symptoms of migraine. It can help with the nasty dizziness I can get as part of a prodrome and has cut the monthly migraine days down from 19 to 10 and they are much milder too. I have recently gone a week without a migraine the first time in years.

My Headache Consultant who covers south east England told me I am the only one of his patients on 10 mg. Everyone else is on 60 mg but we are all different!

Remigepant worked well for a few months but was then useless.

Finally I have also found with Atogepant that when I do get a migraine Sumatriptan is much more effective.
 
forestglip said:
Could you elaborate on why not? It seems important to know if a drug might have side effects that could break blinding.

For example, might nausea clue people in to whether they received the drug?
Click to expand...

The incidences for side effects like nausea quoted are pretty small and don't look likely to be a problem for blinding unless you have a huge trial with very small difference in outcomes across the groups. Goadsby is an intelligent fellow who I would expect to be careful.
 
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