MedicalResearch.com: What is the background for this study? What are the main findings?
Response: This was a post-hoc analysis of Zosano’s pivotal efficacy trial using its adhesive dermally-applied microarray (ADAM) zolmitriptan formulation, M207. The trial found that M207 was effective versus placebo for the co-primary endpoints of pain freedom and most bothersome symptom (MBS) freedom, both at two hours. The MBS endpoint was just ratified as a new endpoint in the FDA’s February 2018 guidance for acute migraine trials. The stated aim of this new endpoint is “…to better align the study outcome with the symptom(s) of primary importance to patients…” This is logical, as a given migraine patient may not experience all four previous symptom endpoints (pain, photophobia, phonophobia, nausea).
MedicalResearch.com: What are the main findings?
- M207 demonstrated freedom from pain and most bothersome symptom at 2 hours
- If performed using this same sample size under the traditional four co-primary endpoints, the trial may not have been positive on the endpoint of phonophobia
- Only one subject who experienced pain freedom at two hours did not also have MBS freedom
- Thus, the use of the new MBS endpoint may allow for smaller and faster trials, in addition to being more relevant to the patient experience
MedicalResearch.com: How will the new FDA guidelines reducing the number of migraine clinical trial endpoints from four to two, potentially allow for a quicker drug development process?
Response: There can be many challenges associated with meeting all previous four endpoints. Some of these challenges stem from the fact that migraine is a complex disease and each subject experiences a migraine differently. Not every subject will experience all four endpoints at the time of treatment, particularly nausea, which results in enhanced placebo response during the trial and drives up patient sample size.
As part of this analysis, we roughly calculated the sample size that would have been required to demonstrate efficacy on all four previous endpoints. At ~170 subjects required per group, this number is over double the 83 per group required to demonstrate efficacy on the new endpoints. Requiring more subjects per group increases the time, duration, complexity and cost of a trial. Thus, reducing this burden could potentially lead to a faster clinical development process.
MedicalResearch.com: What should readers take away from your report?
Response: Key points:
- The most bothersome symptom endpoint appears to be a reasonable and viable alternative to the four co-primary endpoints
- MBS freedom seemed to track very well with pain freedom
- Use of the MBS endpoint in the M207 pivotal trial seems to have resulted in a smaller, and thus quicker and less costly, trial
MedicalResearch.com: What recommendations do you have for future research as a result of this study?
Response:There are multiple ways to capture subjects’ most bothersome symptom. This can be done at baseline (as was done in this trial) using patient recall or done just prior to treatment – which would require a real-time randomization system and for subjects to go home with each possible treatment option. It would be interesting to see if the results of these two strategies differ.
MedicalResearch.com: Is there anything else you would like to add? Any disclosures?
Response: Given that only one subject was pain-free but not most bothersome symptom-free at 2 hours, it would be interesting to examine the feasibility of a single (pain freedom) endpoint in acute migraine trials.
I am an employee of Zosano Pharma.
1. Press Release
Study to Evaluate the Long-Term Safety of M207 in the Acute Treatment of Migraine (ADAM)
The Study is set to complete enrollment on May 18th2018
2. Randomized, Double-blind, Multi-center, Parallel-group, Evaluation of the Safety and Efficacy of ADAM Zolmitriptan for the Acute Treatment of Migraine
ELH Spierings, JL Brandes, DB Kudrow, J Weintraub, J Rubino, DJ Kellerman, SJ Tepper
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