1. ISSN 0017-8748
Headache doi: 10.1111/j.1526-4610.2011.01869.x
© 2011 American Headache Society Published by Wiley Periodicals, Inc.
Research Submissions
MAP0004, Orally Inhaled DHE: A Randomized, Controlled
Study in the Acute Treatment of Migraine head_1869 507..517
Sheena K. Aurora, MD; Stephen D. Silberstein, MD; Shashidhar H. Kori, MD; Stewart J. Tepper, MD;
Scott W. Borland, MS; Min Wang, PhD; David W. Dodick, MD
Objective.—To evaluate the efficacy and tolerability of MAP0004 compared with placebo for a single migraine in adult
migraineurs: The FREEDOM-301 Study.
Background.—Acute treatment of migraine remains a clinical challenge despite the availability of triptans and other
agents. Injectable dihydroergotamine, although effective, is considered invasive and inconvenient, and intranasal dihydroer-
gotamine is associated with inconsistent systemic dosage delivery. MAP0004 is an orally inhaled formulation of dihydroergota-
mine delivered to the systemic circulation. In a phase 2 study, MAP0004 provided significant early onset of pain relief (10
minutes, P < .05) and sustained pain relief for up to 48 hours with a favorable adverse event profile.
Methods.—A phase 3, randomized, double-blind, placebo-controlled, parallel-group, single-attack, outpatient study of
MAP0004, an inhaled dihydroergotamine was conducted at 102 sites in 903 adults with a history of episodic migraine. Patients
were randomized (1:1) to receive MAP0004 (0.63 mg emitted dose; 1.0 mg nominal dose) or placebo, administered after onset
of a migraine headache with moderate to severe pain. The co-primary endpoints were patient-assessed pain relief and absence
of photophobia, phonophobia, and nausea at 2 hours after treatment.
From Swedish Headache Center, Seattle, WA, USA (S.K. Aurora); Jefferson Medical College of Thomas Jefferson University,
Philadelphia, PA, USA (S.D. Silberstein); MAP Pharmaceuticals, Mountain View, CA, USA (S.H. Kori, S.W. Borland, and
M. Wang); Cleveland Clinic, Neurological Center for Pain, Cleveland, OH, USA (S.J. Tepper); Mayo Clinic, Scottsdale, AZ, USA
(D.W. Dodick).
Address all correspondence to S.K. Aurora, Swedish Pain and Headache Center, 1101 Madison Street, Suite 200, Seattle, WA 98104,
USA.
To download a podcast featuring further discussion of this article, please visit www.headachejournal.org
Accepted for publication February 7, 2011.
Conflict of Interest: Dr. Kori, Dr. Wang, and Mr. Borland are employees of MAP and own stock or stock options in MAP. Dr. Aurora
reports having received grants/honoraria from or serving as a consultant or on the advisory board of Advanced Bionics, Alexza,
Allergan, Capnia, GlaxoSmithKline, Kowa, MAP, Merck, Ortho-McNeil, Neuralieve, NuPathe, and Takeda. Dr. Silberstein reports
having received grants or honoraria from Advanced NeuroModulation Systems, AGA, Allergan, Boston Scientific, Capnia,
Coherex, Endo, GlaxoSmithKline, Lilly, MAP, Medtronic, Merck, NuPathe, and Valeant. Dr. Tepper reports having received grants
and research support from ATI, GlaxoSmithKline, MAP, and Merck; serving as a consultant and on the advisory board for GSK,
MAP, Merck, NuPathe, and Zogenix; and serving on the speakers bureau for GlaxoSmithKline, Valeant, and Merck. Dr. Dodick
reports having received honoraria from Allergan, Merck, Neuralieve, Coherex, Kowa, Minster, NeurAxon, H. Lundbeck, Endo,
Pfizer, Eli Lilly, Boston Scientific, Novartis, and MAP in addition to being a consultant to and on the advisory board of these
pharmaceutical companies. He also reports having received research funding from Advanced Neurostimulation Systems and
Medtronic.
Financial Statement: Role of the study sponsor: This research was funded by MAP Pharmaceuticals, Inc. MAP Pharmaceuticals
provided financial and material support, monitoring, data collection and management, and data analysis to the authors and study
investigators.
Clinical Trial Registration: The FREEDOM-301 study was registered at ClinicalTrials.gov (NCT00623636).
507

2. 508 April 2011
Results.—A total of 903 patients (450 active, 453 placebo) were randomized, and 792 (395 active, 397 placebo) experienced
a qualifying migraine. MAP0004 was superior to placebo in all 4 co-primary endpoints: pain relief (58.7% vs 34.5%, P < .0001),
phonophobia free (52.9% vs 33.8%, P < .0001), photophobia free (46.6% vs 27.2%, P < .0001), and nausea free (67.1% vs
58.7%, P = .0210). Additionally, significantly more patients were pain-free at 2 hours following treatment with MAP0004 than
with placebo (28.4% vs 10.1%, P < .0001). MAP0004 was well tolerated; no drug-related serious adverse events occurred.
Conclusions.—In this study, MAP0004 was effective and well tolerated for the acute treatment of migraine with or without
aura, providing statistically significant pain relief and freedom from photophobia, phonophobia, and nausea in adults with
migraine compared with placebo.
Key words: dihydroergotamine, migraine, oral inhalation, MAP0004, sustained pain relief, clinical trial
Abbreviations: AE adverse event, DHE dihydroergotamine, e-diary electronic diary, FEV1 forced expiratory volume at 1
second, ITT intent to treat, SPF sustained pain-free, SPR sustained pain relief
(Headache 2011;51:507-517)
Migraine is common, with US prevalence ~6% in DHE for severe migraines, refractory migraines, and
men and ~18% in women.1,2 It is also debilitating, recurrent headaches,14 and repetitive IV DHE has
resulting in 112 million bedridden days and $13 been reported to relieve symptoms in 90% of those
billion in annual costs to employers.3-5 Underdiagno- with refractory headache, including chronic daily
sis, undertreatment, and inadequate relief with treat- headache with and without medication overuse,
ment are frequently reported despite the availability short-duration headache, and cluster headache.15 IV
of 7 different triptans and other options used for DHE is associated with nausea, frequently necessitat-
acute treatment of migraine.1,6-9 ing pre-administration of antiemetic therapy. The
Patient dissatisfaction with available therapies invasiveness and inconvenience of injectable DHE
for the acute treatment of migraine is high.6,10 In a and inconsistent systemic dosage delivery resulting
questionnaire administered in 3 headache centers to from intranasal DHE administration have limited its
183 patients with migraine diagnosed according to the use for the acute treatment of migraine.14,16
2nd edition of the International Classification of MAP0004 (LEVADEX™, MAP Pharmaceuti-
Headache Disorders (2004),11 96.4% of whom took cals, Mountain View, CA, USA) is a novel formulation
triptans alone or in combination as usual care, slow of DHE delivered by oral inhalation through the
onset of action (37%), inadequate pain relief (42%), lungs to the systemic circulation using the TEMPO®
recurrence/worsening of pain (50%), inability to inhaler (MAP Pharmaceuticals), designed to offer
quickly function normally after taking medication consistent, convenient, and noninvasive dosing.17 The
(48%), and undesirable adverse event (AE) profiles inhaled route of administration may overcome limi-
(38%) were reasons cited for dissatisfaction.6 In light tations of current oral therapies in migraineurs expe-
of these issues, 79% of these patients expressed a riencing gastric stasis, nausea, and vomiting, as well as
willingness to try a new medication to treat their providing more consistent drug delivery than intrana-
migraine headaches.6 Undesirable AEs associated sal administration. In a phase 2 study, MAP0004 pro-
with triptans, collectively known as “triptan sensa- vided a statistically significant early onset of pain
tions,” which may include tingling, paresthesias, chest relief (10 minutes) and meaningful sustained pain
pain or pressure, flushing, dizziness, and sensations of relief (SPR) for up to 48 hours with a favorable AE
warmth involving the head, neck, chest, and extremi- profile,18 including absence of nausea and relative
ties, may be of concern to patients that experience lack of triptan sensation-type AEs. Pharmacokinetic
them.12 studies with MAP0004 have shown that Cmax is
Dihydroergotamine (DHE) has been used effec- reached in ~10 minutes, with a Cmax at least an order of
tively for the acute treatment of migraine since the magnitude lower than with IV DHE but with a
1940s.13 Migraine treatment guidelines recommend similar area under the curve,19 which may account for

3. Headache 509
the observed decrease in concentration-dependent attacks, or seizures were also excluded. Patients with a
AEs with MAP0004 compared with IV DHE.19 history of severe uncontrolled asthma, bronchospasm
The primary objective of this phase 3, double- with inhaled medications, or chronic pulmonary
blind, multicenter FREEDOM-301 study was to disease other than asthma were excluded; however,
evaluate the efficacy and tolerability of orally inhaled patients with controlled asthma were eligible to par-
MAP0004 compared with placebo for the acute treat- ticipate in the trial and were also eligible to participate
ment of a single migraine with or without aura. The in the long-term open-label safety portion of the trial.
0.63 mg emitted dose (1.0 mg nominal dose or 0.5 mg Standard Protocol Approvals, Registrations, and
systemic equivalent) was selected based on prior dose Patient Consents.—The FREEDOM-301 study was
finding studies.18 The nominal dose is the dose conducted in accordance with Good Clinical Prac-
metered out by the canister and delivered from the tices, International Conference on Harmonisation
valve of the device; the emitted dose is that which guidelines, applicable regulatory requirements, and
comes out of the inhaler and is received by the ethical principles of the Declaration of Helsinki of
patient. Efficacy assessments focused on migraine 1975 (as revised in 2000).An appropriate Institutional
symptoms at the 2-hour time point after treatment, as Review Board approved the study protocol at each
is standard in migraine studies evaluating acute phar- clinical site. Written informed consent was obtained
macotherapies. from each potential patient prior to any protocol-
related activities in accordance with Good Clinical
METHODS Practices, the Code of Federal Regulations, and the
Patients.—The study population included 903 male Health Insurance Portability and Accountability Act
and female migraineurs, 18-65 years of age, with a of 1996. The first patient was enrolled in July 2008,
history of episodic migraine with or without aura and the last patient completed study assessments in
according to International Classification of Headache March 2009 at 123 centers in the USA. All study
Disorders-2 criteria.11 Eligible patients must have personnel, patients, monitors, and the sponsor
been diagnosed with migraine for a minimum of 1 remained blinded to treatment assignment until after
year prior to the study and, in the 6 months prior to the database was locked at completion of the double-
the screening visit, suffered from an average of 2-8 blind period. The study was registered at ClinicalTri-
headaches/month. Patients on migraine prophylaxis als.gov (NCT00623636).
and those with a prior history of triptan treatment Procedures.—This study was a phase 3, double-
were eligible for study inclusion. Eligible patients blind, multicenter comparison of MAP0004 0.6 mg
were required to complete a spirometry evaluation, emitted dose (1.0 mg nominal dose or 0.5 mg systemic
with forced expiratory volume at 1 second equivalent) and placebo in the acute treatment of a
(FEV1) Ն50% predicted and FEV1/forced vital single migraine. The double-blind portion of the study
capacity ratio Ն70% predicted. Eligible patients must reported here consisted of 3 clinic visits. During visit
also have had a normal or clinically insignificant 1, patients underwent baseline evaluations, were
electrocardiogram. trained on use of the inhaler and electronic diary
Patients with a known allergy or hypersensitivity (e-diary), and completed the Headache Impact Test
to DHE or who were users of any concomitant questionnaire.20 At visit 2, patients were required to
excluded medication were ineligible. Participation in have reported at least 2 but not more than 8 migraines
another MAP0004 trial, any other clinical trial in the and to have had Ն20 headache-free days on their
past 30 days, or a history of hemiplegic or basilar e-diary during the previous 28-day run-in period.
migraine were causes for exlusion. Patients with Ն2 Patients had to continue to satisfy all eligibility crite-
coronary artery disease risk factors, history of coro- ria to be randomized.
nary artery disease, coronary vasospasm, aortic aneu- Eligible patients were randomly assigned in a 1:1
rysm, peripheral vascular disease or other ischemic ratio without stratification to receive either MAP0004
diseases, or a history of stroke, transient ischemic or placebo. Randomization was centralized and

4. 510 April 2011
performed by an automated interactive voice recog- the 2-hour period; proportion of patients with pain
nition system. Randomized patients were instructed relief at 4 hours; and proportion of patients with pain
to use study drug to treat a single qualifying migraine, relief at 10 minutes. SPR from 2-24 hours was defined
defined by the Headache Classification Committee of as the proportion of patients reporting pain relief at 2
the International Headache Society (2nd edition)11 as hours which was subsequently maintained from 2-24
a migraine with moderate or severe pain (patient hours with no rescue medication use. Time to pain
assessed) that was either unilateral, throbbing (pul- relief was defined as the time when pain relief (mild or
sating), or worsened with activity and occurred in the no pain) was first observed and maintained through 2
presence of either nausea, vomiting, or both phono- hours with no rescue medication use at or prior to this
phobia and photophobia. No triptan or ergot admin- time point. Pain relief at 4 hours and at 10 minutes was
istration was allowed within the 24 hours prior to defined similarly to the 2-hour pain relief endpoint.
migraine onset. The e-diary directed patients to treat Other prespecified endpoints for analysis
if the migraine was qualifying. The active inhaler con- included time to pain freedom in the 2-hour period
tained DHE mesylate suspended in a mixture of posttreatment; proportion of patients pain-free at 2
hydrofluoroalkane propellants, while the placebo hours; proportion of patients with SPR from 2-48
inhaler contained only the hydrofluoroalkane hours posttreatment; and proportion of patients who
mixture. Patients returned for visit 3 for follow-up were sustained pain-free (SPF) from 2-24 hours and
evaluations after treatment, and eligible patients 2-48 hours posttreatment, with no rescue medication
were given the option to continue in a long-term use at or prior to the identified time point. Time to
open-label safety period if required baseline evalua- pain freedom, pain freedom at 2 hours, and SPF were
tions were completed. defined similarly to the time to pain relief, pain relief,
During the double-blind phase, patients recorded and SPR endpoints, respectively, but with a require-
time of onset of their qualifying migraine, severity of ment of no pain.
migraine symptoms, rescue medication use, and pres- Statistical Analysis.—Sample size was determined
ence or absence of allodynia and other migraine using a 2-group continuity corrected chi-square test
attributes at baseline, upon administration of study with a 2-sided, 5% type I error rate based on the
drug, and at several time points up to 48 hours after following assumptions: rates of pain relief of 60% vs
treatment in the e-diary. Pain, nausea, photophobia, 40%, freedom from nausea of 71.5% vs 60%, freedom
and phonophobia were assessed using a 4-point scale from photophobia of 55% vs 40%, and freedom from
for severity (0-no symptoms, 1-mild symptoms, phonophobia of 55% vs 40% for MAP0004 vs
2-moderate symptoms, 3-severe symptoms). All AEs placebo. Assuming a 10% dropout rate at treatment
reported by patients during treatment were recorded, period end, approximately 850 patients were to be
and incidences of serious, severe, and treatment- randomized to obtain 766 treated patients to provide
related AEs were tabulated. an overall 86% power for a 2-sided test with 5% type
Outcome Measures.—This study tested the hypoth- I error rate.
esis that MAP0004 would be superior to placebo for The intent to treat (ITT) population was defined
all 4 co-primary endpoints at the 2-hour time point. as all randomized patients and was primarily used to
These endpoints, derived from US Food and Drug describe patient disposition. The predetermined
Administration requirements for regulatory modified ITT population, defined as all randomized
approval, included the proportion of patients who patients who reported a qualifying migraine, received
achieved pain relief and those who were at least 1 dose of study drug, and reported a posttreat-
photophobia-free, phonophobia-free, and nausea-free ment efficacy evaluation for Ն1 time point at or
at 2 hours posttreatment with no rescue medication before the 2-hour time point, was used for the
use prior to the 2-hour time point. Four secondary primary analysis of efficacy. The safety population
endpoints were also analyzed: proportion of patients consisted of all patients who received 1 dose of study
with SPR from 2-24 hours; time to pain relief during drug and had Ն1 posttreatment safety evaluation.

5. Headache 511
Each co-primary and secondary endpoint was in Figure 1. Baseline demographic, disability, and pul-
tested for treatment effect by comparing MAP0004 monary function measures and migraine characteris-
and placebo-treated patients. A gate-keeping strategy tics at time of treatment were comparable between
was employed to control for the family-wise error the MAP0004 and placebo groups with no baseline
rate of 0.05. If all 4 co-primary endpoints reached discrepancies identified (Table 1). The mean Head-
statistical significance, the first identified secondary ache Impact Test score at baseline was 66, placing
endpoint (proportion of patients with SPR 2-24 patients in the severely impacted range.At the time of
hours) was tested for significance. Sequential signifi- treatment, 55% of patients in the MAP0004 group
cance testing of other secondary endpoints proceeded reported moderate headache pain, 45% reported
only if the preceding endpoint reached significance, severe headache pain, and 55% of patients had
otherwise no further testing was performed. Time to allodynia.
pain relief and freedom were analyzed using a log- Efficacy.—The proportion of patients achieving
rank test and Kaplan-Meier survival analysis tech- each of the 4 co-primary endpoints was statistically
niques. All other prespecified and post hoc endpoints significantly greater for MAP0004 compared with
were analyzed using the Cochran-Mantel-Haenszel placebo at 2 hours posttreatment (Table 2). Pain
test, controlling for each respective baseline score, but relief at 2 hours was observed in 59% of patients in
not adjusted for multiplicity. All endpoints were ana- the MAP0004 group compared with 35% in the
lyzed at a 2-sided, 5% significance level. placebo group (P < .0001, Absolute Risk Reduction
[ARR] = 24%, 95% confidence interval [CI]
RESULTS 17-31%, number-needed-to-treat [NNT] = 4.13). The
A total of 903 patients (450 active, 453 placebo) phonophobia-free rate for MAP0004 compared with
were randomized into the study at 102 US centers, placebo was 53% vs 34% (P < .0001, ARR = 19%,
and 811 experienced a qualifying migraine and self- 95% CI 12-26%, NNT = 5.22), the photophobia-free
treated with study medication. The modified ITT rate was 47% vs 27% (P < .0001, ARR = 19%, 95%
population included 395 patients in the MAP0004 CI 13-26%, NNT = 5.16), and the nausea-free rate
treatment group and 397 patients in the placebo was 67% vs 59% (P = .0210, ARR = 8%, 95% CI
group with randomized patient dispositions as shown 2-15%, NNT = 12.15).
Randomized
n=903
MAP0004 Placebo
ITT population ITT population
n=450 n=453
No qualifying migraine 43
No qualifying migraine 49
Did not receive dose 9
Did not receive dose 6
No follow-up assessment 3
No follow-up assessment 1
mITT Population mITT Population
n=395 n=397
Safety Safety
Population Population
n=404 n=401
Fig 1.—Disposition of randomized patients.

6. 512 April 2011
Table 1.—Baseline Patient Demographics and Characteristics of the Treated Migraine in the Double-Blind Phase
(mITT Population)
MAP0004 (n = 395) Placebo (n = 397)
Baseline
Age, mean (SD), year 40.5 (11.3) 39.6 (11.7)
Female, No. (%) 363 (91.9) 362 (91.2)
Body mass index, mean (SD), kg/m2 28.0 (6.6) 27.9 (6.4)
Race, No. (%)
White 348 (88.1) 335 (84.4)
Black 35 (8.9) 47 (11.8)
Asian 5 (1.3) 12 (3.0)
Other 7 (1.7) 3 (0.8)
HIT-6 score, mean (SD) 65.5 (4.9) 65.6 (5.0)
Percent predicted FEV1, mean (SD) 91.8 (11.9) 92.9 (12.5)
Characteristics of migraine headache at time of treatment, No. (%)
Moderate pain 217 (54.9) 209 (52.6)
Severe pain 178 (45.1) 188 (47.4)
Nausea present 271 (68.6) 280 (70.5)
Photophobia present 380 (96.2) 382 (96.2)
Phonophobia present 364 (92.2) 366 (92.2)
Allodynia present 216 (54.7) 202 (50.9)
FEV1 = forced expiratory volume at 1 second; HIT-6 = Headache Impact Test; mITT = modified intent to treat; SD = standard
deviation.
Table 2.—Proportion of Patients Achieving Co-Primary and Secondary Endpoints (mITT Population)
MAP0004
n/N (%) (Orally Inhaled DHE) Placebo P value
Pain relief
At 10 minutes (all) 33/388 (9) 22/387 (6) .1584
Moderate pain 24/213 (11) 20/200 (10) .6768
Severe pain 9/166 (5) 2/187 (1) .0242
At 2 hours (all) 232/395 (59) 137/397 (35) <.0001
Moderate pain 152/217 (70) 87/209 (42) <.0001
Severe pain 80/178 (45) 50/188 (27) .0003
At 4 hours 254/393 (65) 144/391 (37) <.0001
Time to pain relief* <.05 @ 30 minutes
Sustained pain relief 2-24 h 167/382 (44) 76/387 (20) <.0001
Phonophobia free at 2 h 209/395 (53) 134/397 (34) <.0001
Photophobia free at 2 h 184/395 (47) 108/397 (27) <.0001
Nausea free at 2 h 265/395 (67) 233/397 (59) .0210
*Time to pain relief is the first time at which there was a statistically significant separation of active treatment from placebo that
was also then sustained out to 2 hours.
Bold type indicates a co-primary endpoint.
DHE = dihydroergotamine; mITT = modified intent to treat.

7. Headache 513
The response rates for all 4 secondary endpoints (4%), cough (2%), and vomiting (2%) occurred more
were either statistically or numerically superior for often with MAP0004 than with placebo. In particular,
MAP0004 compared with placebo (Table 2). The SPR incidence of nausea reported as an AE for MAP0004
2-24 hour rate was significantly greater (P < .0001) for was 4% compared with 2% for placebo. Triptan sen-
the MAP0004 group vs the placebo group (Table 2). sations in the MAP0004 group such as chest discom-
Time to onset of pain relief was calculated to be 30 fort (1%), chest pain (0%), and paresthesias (0.5%)
minutes (P = .0266). The proportion of patients expe- were rare and comparable to placebo. Mean change
riencing pain relief at 4 hours was significantly greater in pulmonary function as measured by FEV1 from
(P < .0001) for the MAP0004 group vs the placebo baseline to end of the double-blind period was
group. Finally, the proportion of patients experiencing +0.02 L (0.7% increase) for both treatment groups. A
pain relief at 10 minutes, while not statistically signifi- Ն20% decrease in FEV1 from baseline to end of the
cant, was 50% greater in MAP0004 patients vs double-blind treatment period, considered clinically
placebo patients. relevant, was observed in 4 (1.0%) patients in the
The response rates for several other prespecified MAP0004 group and 3 (0.7%) in the placebo group.
endpoints favored MAP0004 compared with placebo Other evaluations showed no clinically relevant dif-
(as defined by P < .05), without multiplicity adjust- ferences between treatment groups.
ments (Table 3). Two-hour pain relief was significant
with MAP0004 regardless of when treatment DISCUSSION
occurred; within <1 hour and between 1-4 hours after MAP0004 was effective in relieving all symptoms
onset (P < .0001); >4-<8 hours and >8 hours after of migraine with a favorable AE profile in the present
onset (P < .05) compared with placebo. Time to pain study. The 2-hour response rates were similar to or
freedom was 23 minutes (P = .0203). Pain freedom at higher than those reported in recently published
2 hours was 28% for MAP0004 and 10% for placebo phase 3 trials of other migraine investigations, even
(P < .0001). Pain relief at both 24 and 48 hours was though there were more migraineurs treated in
statistically significant for the MAP0004 group vs the this study that had severe pain at the time of
placebo group (57% vs 35% and 49% vs 32%, respec- treatment.21-23 In total, 46.2% of migraineurs in this
tively; P < .0001 for each) (Fig. 2a). Significantly more study reported severe migraine pain, in contrast to
patients in the MAP0004 group achieved pain 36.6% and 40.6% in the reported sumatriptan-
freedom at 24 and 48 hours (48% vs 28% and 45% vs naproxen studies21 and 37.5% and 35.5% in reported
28%, respectively; P < .0001 for each) (Fig. 2b) vs telcagepant trials.22,23
patients receiving placebo. The SPR rate from 2-48 The speed of onset of any given drug is depen-
hours was significantly greater for the MAP0004 dent, at least in part, on its rate of absorption.24 In a
group than for the placebo group, as were the SPF prior study, MAP0004 provided statistically signifi-
2-24 hours and 2-48 hours measures (all P < .0001), as cant pain relief at 10 minutes, which is likely related to
shown in Table 2. Significantly more patients used its rapid absorption through the lung. In the present
rescue medication by 22 hours after treatment in the study, although more patients taking MAP0004
placebo group compared with the MAP0004 group achieved pain relief at 10 minutes compared with
(60% vs 43%, P < .0001). those taking placebo, a statistically significant differ-
Safety and Tolerability.—No drug-related serious ence between the 2 treatments was not evident until
AEs were reported during the study. At least 1 AE 30 minutes. This finding is similar to that found in
was reported in each of 126 patients (31.2%) in the clinical studies of several of the marketed triptans.19
MAP0004 group compared with 101 patients (25.2%) Interestingly, patients who had severe pain at time of
in the placebo group and 140 patients (17.4%; both treatment achieved statistically significant pain relief
treatment groups combined) during the run-in period compared with placebo at 10 minutes. Further studies
(Table 4). Of the AEs that occurred in any treatment to systematically evaluate the onset of action of
group at a rate Ն2%, only product taste (6%), nausea MAP0004 may be warranted, as this pivotal phase 3

8. 514 April 2011
Table 3.—Proportion of Patients Achieving Additional Prespecified Endpoints (mITT Population)
MAP0004
(Orally Inhaled DHE) Placebo P value
Pain relief, n/N (%)
At 30 minutes 111/385 (29) 83/385 (22) .0245
At 60 minutes 187/391 (48) 110/391 (28) <.0001
At 2 hours
Treated within 1 hour of onset 74/112 (66) 48/118 (41) <.0001*
Treated >1-4 hours after onset 91/152 (60) 59/169 (35) <.0001*
Treated >4-< 8 hours after onset 36/68 (53) 16/53 (30) <.05*
Treated >8 hours after onset 26/53 (49) 11/46 (24) <.05*
At 4 hours 254/393 (65) 144/391 (37) <.0001
At 24 hours 218/381 (57) 135/387 (35) <.0001
At 48 hours 174/356 (49) 118/371 (32) <.0001
Pain free, n/N (%)
At 10 minutes 4/369 (1) 2/370 (1) .4350
At 30 minutes 20/385 (5) 5/385 (1) .0024
At 60 minutes 59/391 (15) 18/391 (5) <.0001
At 2 hours 112/395 (28) 40/397 (10) <.0001
At 4 hours 155/394 (39) 65/391 (17) <.0001
At 24 hours 187/386 (48) 108/390 (28) <.0001
At 48 hours 164/367 (45) 107/377 (28) <.0001
Time to pain free‡ <.05 @ 23 minutes
Sustained pain relief 2-48 hours 129/362 (36) 62/376 (17) <.0001
Sustained pain-free
2-24 hours 90/390 (23) 26/390 (7) <.0001
2-48 hours 67/379 (18) 23/389 (6) <.0001
Recurrence
Within 24 hours 15/232 (6) 21/137 (15) .01*
Phonophobia free
At 10 minutes 54/370 (15) 47/369 (13) .5726
At 30 minutes 105/386 (27) 79/384 (21) .0286
At 60 minutes 153/391 (39) 100/391 (26) <.0001
At 4 hours 223/392 (57) 130/390 (33) <.0001
Photophobia free
At 10 minutes 32/370 (9) 26/370 (7) .4460
At 30 minutes 69/386 (18) 53/385 (14) .1237
At 60 minutes 121/391 (31) 85/391 (22) .0032
At 4 hours 206/392 (53) 119/391 (30) <.0001
Nausea free
At 10 minutes 133/370 (36) 126/370 (34) .9409
At 30 minutes 159/386 (41) 182/383 (48) .0169
At 60 minutes 208/391 (53) 214/390 (55) .4028
At 4 hours 251/390 (64) 179/387 (46) <.0001
*
Statistical comparison was not part of the original planned analyses. Analysis performed post hoc without adjustments for multiple
comparisons.
‡Time to pain freedom is the first time at which there was a statistically significant separation of active treatment from placebo that
was also then sustained out to 2 hours.
DHE = dihydroergotamine; mITT = modified intent to treat.
study was not specifically designed to evaluate time of cantly lower recurrence rates were observed after
onset. subcutaneous (SC) DHE treatment in a head-to-head
Dihydroergotamine is generally considered to comparison vs SC sumatriptan.25 Potential explana-
provide prolonged pain relief, and statistically signifi- tions include longer drug half-life, prolonged binding

9. Headache 515
a 100 MAP0004
Placebo
80
†
†
% Patients
†
60
† †
40
*
20
0 33/388 22/387 111/385 83/385 187/391 110/391 232/395 137/397 254/393 144/391 218/381 135/387 174/356 118/371
10 min 30 min 60 min 2 hr 4 hr 24 hr 48 hr
Posttreatment Pain Relief 0-48 Hr
b 100 MAP0004
Placebo
80
% Patients
60
†
†
†
40
†
20 †
*
0 4/369 2/370 20/385 5/385 59/391 18/391 112/395 40/397 155/394 65/391 187/386 108/390 164/367 107/377
10 min 30 min 60 min 2 hr 4 hr 24 hr 48 hr
Posttreatment Pain Freedom 0-48 Hr
Fig 2.—Posttreatment pain relief (a) and pain freedom (b) from 0-48 hours. *P < .05; †P < .0001.
to target receptors, and earlier and more complete cant for MAP0004. Headache recurrence over 24
intervention in the migraine event cascade. The hours, defined as the return of headache to moderate
present data confirm the prolonged effect of DHE. or severe within 24 hours of dosing in subjects who
Both SPR and SPF from 2-24 hours and 2-48 hours had pain relief within 2 hours of dosing, was 6% for
were significant for MAP0004 compared with placebo MAP0004 and 15% for placebo.
(all P < .0001), illustrating this effect. The SPF 2- to MAP0004 was well tolerated in this study. As
24-hour therapeutic gain observed with MAP0004 anticipated, the rate of nausea was low. The low rate
was 16% and is similar to 2- to 24-hour SPF values of AEs observed here is similar to that seen in previ-
observed in phase 3 trials of sumatriptan/naproxen ous studies18,19,26 with MAP0004 and may be
and telcagepant.21,22 SPR 2-48 and SPF 2-48 hour rates explained by the pharmacokinetic profile and the
are rarely reported but were both statistically signifi- lower Cmax of orally inhaled DHE compared with IV

10. 516 April 2011
Table 4.—Incidence of Adverse Events Occurring in Ն2% of Patients During the Run-In Period and During Double-Blind
Treatment With MAP0004 and Placebo
No. (%) of Patients
Adverse Event Run-In Period (n = 805) MAP0004 (n = 404) Placebo (n = 401)
Any event 140 (17.4) 126 (31.2) 101 (25.2)
Cough 4 (0.5) 10 (2.5) 5 (1.2)
Nasopharyngitis 14 (1.7) 8 (2.0) 14 (3.5)
Nausea 1 (0.1) 18 (4.5) 8 (2.0)
Product taste 0 26 (6.4) 7 (1.7)
Upper respiratory tract infection 22 (2.7) 12 (3.0) 12 (3.0)
Vomiting 1 (0.1) 8 (2.0) 3 (0.7)
DHE.18 Triptan sensations including chest pain, chest Category 2
discomfort, paresthesias, and flushing were rare. Lack (a) Drafting the Manuscript
of statistically significant changes in pulmonary func- Shashidhar H. Kori; Scott W. Borland; Sheena K.
tion and laboratory measures support the safety of Aurora
the inhaled route as an alternative to address limita- (b) Revising It for Intellectual Content
tions of oral, nasal, and injectable/IV therapies. Stephen D. Silberstein; David W. Dodick; Stewart
An open-label extension portion of this study J. Tepper
examining long-term safety is ongoing, and additional
Category 3
studies are planned to further evaluate the efficacy,
(a) Final Approval of the Completed Manuscript
tolerability, and safety profile of MAP0004.
Sheena K. Aurora; Shashidhar H. Kori; Stephen
Acknowledgments: The authors thank John
D. Silberstein; David W. Dodick; Stewart J.
Simmons, MD, for editorial assistance with manuscript
Tepper; Scott W. Borland; Min Wang
preparation. Dr. Kori and Mr. Borland prepared the first
draft of the manuscript with critical revisions by all of the
authors for important intellectual content. Dr. Aurora had REFERENCES
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