PDF: ZOTRIP (Post-Hoc)
(2018)Objective
To evaluate the utility of using pain freedom and most bothersome symptom (MBS) freedom as co-primary endpoints in acute migraine trials, via post-hoc analysis of the ZOTRIP trial of ADAM zolmitriptan 3.8 mg
Study Summary
• 159 patients (82 ADAM zolmitriptan 3.8 mg, 77 placebo) from the original 365 randomized; MBS prespecified as photophobia (50%), phonophobia (27%), or nausea (23%)
• MBS freedom and pain freedom were highly concordant — only 1 patient (<1%) achieved pain freedom without MBS freedom; 28% achieved MBS freedom without pain freedom
• MBS as a co-primary endpoint was feasible and may allow smaller, faster trials compared to requiring significance on all 4 traditional endpoints
Intervention
ADAM (adhesive dermally applied microarray) zolmitriptan 3.8 mg intracutaneous patch vs placebo (from the parent ZOTRIP trial; this post-hoc analysis used only the 3.8 mg and placebo arms)
Study Design
Arms: 2 (post-hoc analysis subset): ADAM zolmitriptan 3.8 mg vs Placebo (original ZOTRIP had 4 arms: 1 mg, 1.9 mg, 3.8 mg, placebo)
Patients per Arm: 82 ADAM zolmitriptan 3.8 mg, 77 placebo (159 total in post-hoc analysis; 365 randomized in original trial)
Outcome
• By MBS subgroup — Photophobia: pain-free 36% vs 14% (P = .02), MBS-free 67% vs 35% (P < .01); Nausea: pain-free 56% vs 16% (P = .01), MBS-free 89% vs 58% (P = .04); Phonophobia: pain-free 41% vs 14% (P = .05), MBS-free 55% vs 43% (P = .45, NS)
• Using traditional 4 co-primary endpoints: pain relief 80% vs 59% (P < .01), photophobia-free 70% vs 42% (P < .01), nausea-free 82% vs 64% (P = .01), phonophobia-free 70% vs 56% (P = .06, NS)
Bottom Line
The use of a pre-specified Most Bothersome Symptom (MBS) as a co-primary endpoint was feasible and compared favorably to the traditional four co-primary endpoints. In the ZOTRIP trial, ADAM zolmitriptan 3.8 mg was effective for both pain freedom and MBS freedom at 2 hours, and achieving pain freedom was highly concordant with achieving MBS freedom.
Major Points
- This paper is a post-hoc analysis of the ZOTRIP trial, a pivotal phase 2b/3 study of an adhesive dermally applied microarray (ADAM) for zolmitriptan delivery.
- ZOTRIP was one of the first major trials to adopt the FDA's new guidance of using two co-primary endpoints: pain freedom at 2 hours and freedom from the most bothersome symptom (MBS) at 2 hours.
- Patients prospectively designated their MBS as either photophobia (50%), phonophobia (27%), or nausea (23%).
- The original trial found that ADAM zolmitriptan 3.8 mg was significantly superior to placebo for both 2-hour pain freedom (42% vs 14%; P<.01) and 2-hour MBS freedom (68% vs 43%; P<.01).
- This analysis showed a very high concordance between the two endpoints; only 1 patient (1%) achieved pain freedom without also achieving MBS freedom, whereas 28% achieved MBS freedom without pain freedom.
- The use of the MBS endpoint may allow for smaller and more efficient trials compared to the previous standard of four co-primary endpoints.
Study Design
- Study Type
- Post-hoc analysis of a multicenter, randomized, double-blind, placebo-controlled, parallel-group, Phase 2b/3 trial
- Randomization
- Yes
- Blinding
- Double-blind
- Sample Size
- 159
- Follow-up
- Assessed at multiple time points up to 24 hours
- Centers
- 36
- Countries
- United States
Primary Outcome
Definition: Co-primary endpoints of the ZOTRIP trial: 1) proportion of patients with pain freedom at 2 hours and 2) proportion with freedom from their most bothersome symptom (MBS) at 2 hours.
| Control | Intervention | HR/OR | P-value |
|---|---|---|---|
| Pain Freedom: 14%; MBS Freedom: 43% | Pain Freedom: 42%; MBS Freedom: 68% | - | <.01 for both endpoints |
Limitations & Criticisms
- The primary limitation is the post-hoc nature of the analysis.
- The results should be considered preliminary and require confirmation in larger, prospectively designed studies to validate the utility of the MBS endpoint.
Citation
Headache 2018;58:986-992