MAP0004, Orally Inhaled DHE

A Randomized, Controlled Study in the Acute Treatment of Migraine

Sheena K. Aurora, MD; Stephen D. Silberstein, MD; Shashidhar H. Kori, MD; Stewart J. Tepper, MD; ScottW. Borland, MS; Min Wang, PhD; DavidW. Dodick, MD

Disclosures

Headache. 2011;51(4):507-517. 

In This Article

Results

A total of 903 patients (450 active, 453 placebo) were randomized into the study at 102 US centers, and 811 experienced a qualifying migraine and self-treated with study medication. The modified ITT population included 395 patients in the MAP0004 treatment group and 397 patients in the placebo group with randomized patient dispositions as shown in Figure 1. Baseline demographic, disability, and pulmonary function measures and migraine characteristics at time of treatment were comparable between the MAP0004 and placebo groups with no baseline discrepancies identified (Table 1). The mean Headache Impact Test score at baseline was 66, placing patients in the severely impacted range. At the time of treatment, 55% of patients in the MAP0004 group reported moderate headache pain, 45% reported severe headache pain, and 55% of patients had allodynia.

Figure 1.

Disposition of randomized patients.

Efficacy

The proportion of patients achieving each of the 4 co-primary endpoints was statistically significantly greater for MAP0004 compared with placebo at 2 hours posttreatment (Table 2). Pain relief at 2 hours was observed in 59% of patients in the MAP0004 group compared with 35% in the placebo group (P < .0001, Absolute Risk Reduction [ARR] = 24%, 95% confidence interval [CI] 17–31%, number-needed-to-treat [NNT] = 4.13). The phonophobia-free rate for MAP0004 compared with placebo was 53% vs 34% (P < .0001, ARR = 19%, 95% CI 12–26%, NNT = 5.22), the photophobia-free rate was 47% vs 27% (P < .0001, ARR = 19%, 95% CI 13–26%, NNT = 5.16), and the nausea-free rate was 67% vs 59% (P = .0210, ARR = 8%, 95% CI 2–15%, NNT = 12.15).

The response rates for all 4 secondary endpoints were either statistically or numerically superior for MAP0004 compared with placebo (Table 2). The SPR 2–24 hour rate was significantly greater (P < .0001) for the MAP0004 group vs the placebo group (Table 2). Time to onset of pain relief was calculated to be 30 minutes (P = .0266). The proportion of patients experiencing pain relief at 4 hours was significantly greater (P < .0001) for the MAP0004 group vs the placebo group. Finally, the proportion of patients experiencing pain relief at 10 minutes, while not statistically significant, was 50% greater in MAP0004 patients vs placebo patients.

The response rates for several other prespecified endpoints favored MAP0004 compared with placebo (as defined by P < .05), without multiplicity adjustments (Table 3). Two-hour pain relief was significant with MAP0004 regardless of when treatment occurred; within <1 hour and between 1–4 hours after onset (P < .0001); >4-<8 hours and >8 hours after onset (P < .05) compared with placebo. Time to pain freedom was 23 minutes (P = .0203). Pain freedom at 2 hours was 28% for MAP0004 and 10% for placebo (P < .0001). Pain relief at both 24 and 48 hours was statistically significant for the MAP0004 group vs the placebo group (57% vs 35% and 49% vs 32%, respectively; P < .0001 for each) (Fig. 2a). Significantly more patients in the MAP0004 group achieved pain freedom at 24 and 48 hours (48% vs 28% and 45% vs 28%, respectively; P < .0001 for each) (Fig. 2b) vs patients receiving placebo. The SPR rate from 2–48 hours was significantly greater for the MAP0004 group than for the placebo group, as were the SPF 2–24 hours and 2–48 hours measures (all P < .0001), as shown in Table 2. Significantly more patients used rescue medication by 22 hours after treatment in the placebo group compared with the MAP0004 group (60% vs 43%, P < .0001).

Figure 2.

Posttreatment pain relief (a) and pain freedom (b) from 0–48 hours. *P < .05; †P < .0001.

Safety and Tolerability

No drug-related serious AEs were reported during the study. At least 1 AE was reported in each of 126 patients (31.2%) in the MAP0004 group compared with 101 patients (25.2%) in the placebo group and 140 patients (17.4%; both treatment groups combined) during the run-in period (Table 4). Of the AEs that occurred in any treatment group at a rate ≥2%, only product taste (6%), nausea (4%), cough (2%), and vomiting (2%) occurred more often with MAP0004 than with placebo. In particular, incidence of nausea reported as an AE for MAP0004 was 4% compared with 2% for placebo. Triptan sensations in the MAP0004 group such as chest discomfort (1%), chest pain (0%), and paresthesias (0.5%) were rare and comparable to placebo. Mean change in pulmonary function as measured by FEV1 from baseline to end of the double-blind period was +0.02 L (0.7% increase) for both treatment groups. A ≥20% decrease in FEV1 from baseline to end of the double-blind treatment period, considered clinically relevant, was observed in 4 (1.0%) patients in the MAP0004 group and 3 (0.7%) in the placebo group. Other evaluations showed no clinically relevant differences between treatment groups.

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