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ISSN 0017-8748
doi: 10.1111/head.13199
Published by Wiley Periodicals, Inc.
Headache
C 2017 American Headache Society
V
Research Submissions
AVP-825 (Sumatriptan Nasal Powder) Reduces Nausea
Compared to Sumatriptan Tablets: Results of the COMPASS
Randomized Clinical Trial
Richard B. Lipton, MD; James S. McGinley, PhD; Kenneth J. Shulman, DO;
Stephen D. Silberstein, MD; R. J. Wirth, PhD; Dawn C. Buse, PhD
Background.—Migraine-related nausea is associated with significant disability, increased burden of disease, and personal distress. Nausea can lead to delays or avoidance of initiating oral migraine treatment, sometimes resulting in treatment failures and poor outcomes. Nausea is often a symptom of migraine, but nausea may also be a consequence of
treatment (ie, treatment emergent nausea [TEN]). Relieving nausea and minimizing TEN are important goals in acute
migraine therapy.
Methods.—We analyzed data from the COMPASS study, a randomized, double blind, double-dummy, comparative efficacy study that contrasted two active treatments, AVP-825 (breath-powered intranasal delivery of powdered sumatriptan
22 mg) and oral sumatriptan tablets (100 mg). Three-level logistic multilevel models were used to examine longitudinal changes
in nausea from three distinct perspectives across multiple attacks. Model 1 (Overall Nausea) examined longitudinal change in
nausea from pre-dose through 120 minutes post-dose for the entire sample, independent of baseline nausea. Model 2 examined
TEN from 10 minutes through 120 minutes post-dose in attacks free of nausea at baseline to investigate whether or not nausea
developed following treatment. Model 3 examined Nausea Relief from 10 minutes through 120 minutes post-dose in eligible
attacks with nausea at baseline to examine whether or not nausea was relieved over the first 2 hours post-dose. Models tested
for differences in rate of change in nausea over time and odds of nausea at specific time-points.
Results.—Longitudinal nausea trajectories differed for AVP-825 and oral sumatriptan in the Overall Nausea model
(Model 1) and TEN model (Model 2), but were more comparable across treatments for the Nausea Relief (Model 3).
More specifically, in the Overall Nausea model (Model 1), an individual treating an attack with AVP-825 had a significantly faster decrease in nausea through the first 60 minutes post-dose and reduced odds of nausea at each time-point from
30 minutes through 120 minutes post-dose compared to oral sumatriptan. In Model 2, an individual’s risk for TEN
increased at a significantly faster rate through the first 45 minutes post-dose when treating an attack with oral sumatriptan,
with significantly greater odds of experiencing TEN at 45, 60, and 90 minutes post-dose compared to AVP-825. The Nausea
Relief model (Model 3) showed similar rates of change in nausea over time for the two treatments, but there was a constant difference in nausea level leading to reduced odds of nausea when treating with AVP-825 compared to oral
sumatriptan.
Conclusions.—All three longitudinal models showed that AVP-825 had more favorable nausea outcomes compared to
oral sumatriptan. AVP-825 treatment led to more rapid early reductions in Overall Nausea rates during the first hour,
From the Department of Neurology Albert Einstein College of Medicine and Montefiore Headache Center, Bronx, NY, USA
(R.B. Lipton and D.C. Buse); Department of Epidemiology and Population Health, Albert Einstein College of Medicine,
Bronx, NY, USA (R.B. Lipton); Montefiore Medical Center, Bronx, NY, USA (R.B. Lipton and D.C. Buse); Vector Psychometric Group, LLC, Chapel Hill, NC, USA (J.S. McGinley and R.J. Wirth); Avanir Pharmaceuticals, Inc., Aliso Viejo, CA,
USA (K.J. Shulman); Thomas Jefferson University, Philadelphia, PA, USA (S.D. Silberstein).
Address all correspondence to Richard Lipton, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Van Etten
3C12, Bronx, NY, USA, email: richard.lipton@einstein.yu.edu
Accepted for publication August 22, 2017.
1
2
Month 2017
reduced odds of nausea from 30 minutes to 2 hours following treatment and reduced risk of TEN compared to oral sumatriptan. These results highlight the importance of separately assessing TEN and Nausea Relief in acute treatment trials of
migraine.
Key words: nausea, migraine, sumatriptan, triptan, disability
(Headache 2017;00:00-00)
INTRODUCTION
Migraine is a neurobiological disorder characterized by recurrent episodes of headache and associated symptoms, including nausea, sensitivity to light,
and to sound.1 Nausea is an important determinant
of the migraine burden because it is common, disabling, and associated with poor outcomes for both
individual attacks and for particular patients.2-4
Roughly half of people with migraine experience
nausea with at least half of their attacks.2,5 Persons
with migraine and nausea have substantially higher
levels of attack-related disability than persons without nausea.2 A large population-based longitudinal
study found that people with episodic migraine and
frequent nausea progressed to chronic migraine at
twice the rate of those with no or low frequency
nausea.4 These results persisted after adjusting for
headache-related disability, psychiatric comorbidities, and patterns of medication. Thus, nausea is
important as a diagnostic feature of migraine, as a
target of treatment, and as a factor which should be
considered when choosing treatments for specific
patients and attacks. The experience and timing of
nausea in the migraine attack varies both within and
among individuals. Nausea may develop before,
after, or at the same time as headache.6,7 Potential
mechanisms for migraine associated nausea include
dysfunction of the central modulation of multisensory afferents and autonomic dysfunction, which
may be associated with gastric paresis.6,8 Gastric
paresis during migraine attacks is relevant to acute
therapy because it may cause poor absorption of
oral medications.9
Triptans are the most widely used acute prescription medications for the acute treatment of
migraine and are the treatment of choice for people
with significant migraine-related disability.10-12 Triptans are safe and effective; they relieve pain,
Conflict of Interest: Dr. Richard B. Lipton is the Edwin S. Lowe Professor of Neurology at the Albert Einstein College of
Medicine in New York. He receives research support from the National Institutes of Health (NIH): 2PO1 AG003949 (Program
Director), 5U10 NS077308 (PI), 1RO1 AG042595 (Investigator), RO1 NS082432 (Investigator), K23 NS09610 (Mentor),
K23AG049466 (Mentor). He also receives support from the Migraine Research Foundation and the National Headache Foundation. He serves on the editorial board of Neurology and as senior advisor to Headache. He has reviewed for the NIA and
NINDS, holds stock options in eNeura Therapeutics; serves as consultant, advisory board member, or has received honoraria
from: American Academy of Neurology, Alder, Allergan, American Headache Society, Amgen, Autonomic Technologies,
Avanir, Biohaven, Biovision, Boston Scientific, Colucid, Dr. Reddy’s, Electrocore, Eli Lilly, eNeura Therapeutics, GlaxoSmithKline (formerly Novartis), Merck, Pernix, Pfizer, Supernus, Teva, Trigemina, Vector, Vedanta. He receives royalties from
Wolff’s Headache, 8th Edition, Oxford Press University, 2009, Wiley and Informa. James S. McGinley, PhD, is an employee
of Vector Psychometric Group, LLC (VPG). VPG received compensation for this work from Avanir Pharmaceuticals, Inc.,
Aliso Viejo, CA. Kenneth J. Shulman, MD, is an employee of Avanir Pharmaceuticals, Inc. Stephen D. Silberstein, MD,
receives, or has received, honoraria from Alder Biopharmaceuticals. Allergan, Inc., Amgen. Avanir Pharmaceuticals, Inc., Curelator, Inc., Depomed. Dr. Reddy’s Laboratories. eNeura Inc., electroCore Medical, LLC. INSYS Therapeutics. Labrys Biologics. Lilly USA, LLC. Medscape, LLC. Medtronic, Inc., Neuralieve; NINDS. Pfizer, Inc., Supernus Pharmaceuticals, Inc., Teva
Pharmaceuticals. Theranica. and Trigemina, Inc., as a consultant and/or advisory panel member. R.J. Wirth, PhD, is an
employee of Vector Psychometric Group, LLC (VPG). VPG received compensation for this work from Avanir Pharmaceuticals, Inc., Aliso Viejo, CA. Dawn C. Buse, PhD, has received grant support and honoraria from Allergan, Amgen, Avanir,
Biohaven, Eli Lilly and Promeius. She is an employee of Montefiore Medical Center, which has received research support
from Allergan, Alder, Avanir, CoLucid, Dr. Reddy’s, Endo Pharmaceuticals, GlaxoSmithKline, Labrys, MAP Pharmaceuticals,
Merck, NuPathe, Novartis, Ortho-McNeil, and Zogenix, via grants to the National Headache Foundation and/or Montefiore
Medical Center. She is on the editorial board of Current Pain and Headache Reports, the Journal of Headache and Pain, Pain
Medicine News, and Pain Pathways magazine.
Funding: Manuscript Funding Provided by Avanir Pharmaceuticals, Inc., Aliso Viejo, CA.
Headache
3
nausea, and other associated symptoms when given by
oral and non-oral routes.9 People who experience nausea at migraine baseline are less likely to respond to
oral triptans,13 and nausea associated with a migraine
may lead individuals to delay or avoid oral treatment.9
In some cases, triptans may actually cause treatment
emergent nausea (TEN).14,15 For these reasons,
migraine treatment guidelines recommend that nonoral formulations should be considered for migraine
attacks associated with nausea and/or vomiting.16
Most clinical trials assessing nausea compare
the proportion of patients free of the symptom 2
hours post-treatment with an active drug or a comparator. Though this approach demonstrates the
benefits of triptan therapy, it does not differentiate
outcomes in attacks with nausea at baseline from
those without nausea at baseline. In attacks with
nausea at baseline, it is helpful to measure relief of
nausea. Attacks free of nausea at baseline may
remain nausea free or develop TEN. TEN may
arise either as a side effect of medication or as a
consequence of an evolving migraine attack.
Investigators have attempted to disaggregate
nausea relief in those who have it at baseline and
in those free of it at baseline who experience the
emergence of nausea following treatment. In a post
hoc analysis of several clinical trials, Lipton et al
examined the rates of TEN for a number of triptans and placebo.13 TEN occurred in about onefifth of patients treated with oral sumatriptan and
in just one-tenth of placebo-treated patients.17 The
hypothesis that this is a sumatriptan-related adverse
effect which may arise from direct gastric effects
of medication on the gut17 is consistent with the
absence of TEN when sumatriptan is administered
by non-oral routes, including subcutaneous injection
and delivery via an iontophoretic patch.15,18 Under
this hypothesis, we would predict that other nonoral routes of sumatriptan administration should
also result in low rates of TEN.
A non-oral delivery system for sumatriptan is
provided by AVP-825 (OnzetraV XsailV ). This
Breath PoweredV intranasal delivery system contains 22 mg of sumatriptan as a dry powder and
uses the patient’s own breath to deliver medication
beyond the nasal valve to the upper posterior nasal
R
R
R
cavity, a large area lined with richly vascular
mucosa conducive to rapid drug absorption into the
systemic circulation.19 Compared to sumatriptan
100 mg oral tablet and 20 mg nasal spray, AVP-825
has a shorter time to maximal plasma concentration
(Tmax) and greater exposure in the first 15 minutes
(AUC0-15 minutes) post-dose. This PK profile suggests
that AVP-825 is a more efficient way of delivering
sumatriptan, which may offer more rapid relief of
migraine pain than oral sumatriptan, a conclusion
directly supported by the COMPASS and TARGET
trials.20-23 COMPASS was a randomized, double
blind, double-dummy, comparative efficacy study
that contrasted two active treatments, AVP-825 and
oral sumatriptan tablets (100 mg). Participants
treated up to five attacks with each treatment and
assessed both pain and nausea at multiple early
endpoints.
We conducted a post hoc analysis of data from
the COMPASS study to characterize the longitudinal trajectories of nausea from three unique perspectives, and to compare treatment differences
between AVP-825 and oral sumatriptan using two
comparative efficacy hypotheses: (1) AVP-825 will
more rapidly reduce nausea compared to oral
sumatriptan, and (2) Oral sumatriptan will produce
higher rates of TEN than AVP-825. The COMPASS study is ideal to test these hypotheses for
several reasons. First, AVP-825 is rapidly absorbed
and so might be expected to rapidly relieve nausea.
Second, AVP-825 is primarily absorbed across the
mucosa of the posterior nasopharynx, avoiding
TEN by circumventing the gut more than oral therapy. Third, the unique repeated attack, crossover
study design instructed participants to treat up to
five attacks with each active treatment. This enables
us to obtain more stable estimates of treatment
effects and to partition the total variation in nausea
into components due to within person and between
person differences.
METHODS
COMPASS Study Design.—Detailed methodology for the COMPASS study (NCT01667679, clinicaltrials.gov) has been previously published.20
Briefly, the COMPASS study was a randomized,
4
Month 2017
AVP-825 +
Placebo Tablet
AVP-825 +
Placebo Tablet
Fig. 1.—Study flowchart.
double-blind, double-dummy, multiple attack,
active-comparator crossover study conducted at 20
outpatient headache centers throughout the United
States from August 2012 to March 2014. This study
was approved by New England Independent
Review Board (NEIRB.com, Newton, MA) as well
as additional Institutional Review Boards at three
institutions (Mayo Clinic, Cleveland Clinic, and
Thomas Jefferson University). Written informed
consent was obtained from each subject prior to
protocol-related activities.
Participants were randomized 1:1 to one of two
blinded treatment sequences, each of which had
two 12-week treatment periods. For treatment
sequence 1, patients treated up to five attacks in
the first treatment period with AVP-825 and a placebo tablet (Ranbaxy Pharmaceuticals Inc., Jacksonville, FL). After 3 months or five attacks treated
(whichever was first), sequence 1 patients began the
second treatment period and received an AVP-825
placebo (containing lactose powder) plus a 100 mg
sumatriptan tablet. For participants in treatment
sequence 2, treatment order was reversed as
depicted in Figure 1.
Qualifying migraine attacks had to meet
ICHD-2 criteria for migraine24 and had to have
pain of at least mild intensity. Treatment within 1
hour of attack onset was required, and subjects
recorded outcomes for each attack in an electronic
diary. A second dose of study drug was allowed
after the 2-hour assessments were completed and
up to 24 hours after the first dose if there was no
relief or the headache worsened/recurred. Rescue
medication was also permitted if there was no relief
or headache worsened/recurred 2 hours or more
after the second dose. Subjects were withdrawn
from the study for failure to treat any migraine
headaches over the 12 weeks of treatment period 1
or treatment period 2.
Subjects.—Participants were recruited from outpatient headache centers in the US, 18-65 years
old, met International Classification of Headache
Disorders, 2nd Edition, 1st revision (ICHD-II) criteria for migraine with or without aura24 and had a
migraine attack frequency from two to eight per
month with <15 headache days per month for 1
year prior to screening. Participants were excluded
if they were unable to distinguish migraine from
other headache types, if they had 15 or more days
per month, or if they had a history of nonresponse
to an adequate dose and duration of treatment with
sumatriptan or two other triptans. Persons whose
Headache
migraine preventive medications had been adjusted
in the past 4 weeks were also excluded. Other medical and psychological conditions that may affect
patient safety or study outcomes also led to
exclusion.
Variables.—The primary outcome for these analyses was a binary nausea measure (0 5 No nausea,
1 5 Nausea) reported at pre-dose and 10, 15, 30, 45,
60, 90, and 120 minutes post-dose for each attack.
Covariates included in the statistical models were
treatment, treatment period, treatment sequence,
age, gender, race, and time.
Analyses.—The current study utilized all available data to examine longitudinal change in nausea.
All analyses were conducted using PROC GLIMMIX in SAS 9.4. Three-level logistic multilevel
models, estimated with maximum likelihood, evaluated how nausea unfolds over time in individuals
across multiple attacks. The three-level multilevel
models explicitly accounted for the COMPASS
study design, which had repeated measures (level
1) nested within each attack (level 2), and multiple
attacks nested within each subject (level 3). Each
of the fitted multilevel models included both random attack (level 2) and random subject effects
(level 3). These random effects allowed nausea to
vary both across attacks (within subjects) and
between subjects. These models result in subjectspecific interpretations; see further details in the
work by Fitzmaurice et al. and Hedeker and
Gibbons.25,26
Three separate statistical models were used to
examine unique aspects of nausea. Model 1 examined longitudinal change in Overall Nausea. This
model tested how patients’ propensity for nausea
changed over the first 2 hours (pre-dose through 2
hours post-dose) across treatments regardless of
whether or not they reported baseline nausea.
Model 2 examined TEN in eligible attacks free of
nausea at baseline to explore whether or not nausea developed following treatment. This model
tested treatment differences in TEN from 10
minutes through 2 hours post-dose, since eligible
attacks were without baseline nausea. Model 3
examined Nausea Relief, testing treatment differences in nausea from 10 minutes through 2 hours
5
for attacks with baseline nausea. For all models, we
examined several function forms for nausea trajectories over time including linear, polynomial (eg,
quadratic, cubic), and spline (piecewise) trends. We
ultimately used polynomial time trends for all three
models: The Overall Nausea model (Model 1) used
a quadratic time trend while the TEN (Model 2)
and Nausea Relief models (Model 3) used a cubic
functional form for time. The polynomial terms
allowed for nonlinear changes in nausea over time.
More specifically, the quadratic trend (squaredterm) permitted rate of change to differ over time
(ie, acceleration/deceleration) and the cubic trend
allowed for change in acceleration/deceleration
(ie, in physics this is referred to as a “jerk”). Thus,
these polynomial terms more accurately captured
how nausea risk was changing throughout the
course of attacks.
A benefit of our modeling strategy was that the
nonlinear longitudinal changes in nausea could be
described using instantaneous rates of change
(IROC), which represent how much nausea is
changing for an individual at a given point in time.
A superior treatment should show faster rates of
decrease in nausea which is represented by a more
negative IROC. Consistent with standard analyses
of clinical trial data, we also test model-implied
treatment differences of an individual’s odds of
nausea at each fixed time-point (ie, level differences). Using multilevel modeling, the total variance in nausea could also be separated into that
which is due to within attack (level 1), between
attack (within subject) (level 2), and between subject (level 3) differences. For instance, the proportion of variance between
attacks within subjects is
ð2Þ
ð3Þ
ð2Þ
p2
s00 = s00 1s00 1 3 and the
proportion
of variance
2
ð3Þ
ð3Þ
ð2Þ
ð3Þ
between subjects is s00 = s00 1s00 1 p3 , where s00
ð2Þ
is the level 3 subject random effect variance, s00 is
2
the level 2 attack random effect variance, and p3 is
the variance of the standard logistic distribution (ie,
level 1 repeated measures); see the work by
Hedeker and Gibbons26 or Raudenbush et al27 for
more details on variance decomposition. In the current study, we computed these values based on the
estimated variance components from the final conditional models.
6
Month 2017
Table 1.—Demographic Characteristics for Each Subsample
Population
N
Model 2: TEN
Model 3: Nausea Relief
Individuals with no Individuals with nausea
Model 1: Overall Nausea nausea at baseline
at baseline for at least
Total sample
for at least one attack
one attack
N 5 259
N 5 232
N 5 167
Mean (SD) or %
Mean (SD) or %
Mean (SD) or %
Sociodemographics
Age
Male
White
Historic symptoms prior to study
Migraine attacks per month (past 12 mo.)
Has monthly migraine moderate severity
Historic pain intensity of treated migraine headaches
None
Mild
Moderate
Severe
Migraine type (past 12 mo.)
Aura only
With aura
Without aura
Presence of (past 6 mo.)
Vomiting
Nausea
None
Mild
Moderate
Severe
Photophobia
None
Mild
Moderate
Severe
Phonophobia
None
Mild
Moderate
Severe
Attacks treated attacks during the COMPASS study
Number of attacks per patient
Total attacks
RESULTS
Demographics.—Table 1 shows the demographic
characteristics for the samples used for each of the
three nausea models. The Overall Nausea model
(Model 1) included 259 individuals with an average
of 6.8 attacks each for a total of 1751 attacks. The
TEN model (Model 2) included attacks free of nausea at baseline; there were 232 individuals with an
average of 4.9 nausea free attacks each for a total
of 1146 attacks. The Nausea Relief model (Model
40.0 (12.3)
15.4
78.4
40.2 (12.1)
15.9
78.4
40.5 (12.4)
12.0
79.0
4.9 (1.9)
100.0
4.9 (1.9)
100.0
4.9 (1.9)
100.0
5.0
43.0
40.7
11.2
5.2
42.0
41.6
11.3
5.4
39.8
42.8
12.1
1.2
32.8
77.2
0.8
33.6
75.9
1.2
33.5
77.8
35.9
33.6
43.7
15.8
32.4
37.8
13.9
17.7
34.5
35.3
12.5
4.8
29.3
45.5
20.4
1.5
12.7
42.1
43.6
1.7
14.2
40.1
44.0
1.2
12.0
38.3
48.5
5.0
17.8
43.6
33.6
5.2
17.2
44.8
32.8
5.4
16.2
41.9
36.5
6.8 (3.3)
1751
4.9 (3.0)
1146
3.5 (2.6)
579
3) included attacks with nausea at baseline; there
were 167 individuals with an average of 3.5 attacks
each for a total of 579 attacks. Across the three
models, samples had similar distributions of demographic characteristics, where the mean age of participants was 40, 12%-16% were male, and 78%79% were white. All participants reported monthly
migraines of at least moderate severity over the 12
months prior to entering the study, but only 52%55% of participants reported taking medication
Headache
7
b: Treatment Emergent Nausea
1.5
1.5
0.5
0.5
Nausea
Nausea
a: Overall Nausea
-0.5
-1.5
-0.5
-1.5
-2.5
-2.5
-3.5
-3.5
0
10 20 30 40 50 60 70 80 90 100 110 120
10 20 30 40 50 60 70 80 90 100 110 120
Time
Time
Oral Sumatriptan
Oral Sumatriptan
AVP-825
1.5
AVP-825
c: Nausea Relief
Nausea
0.5
-0.5
-1.5
-2.5
-3.5
10 20 30 40 50 60 70 80 90 100 110 120
Time
Oral Sumatriptan
AVP-825
Fig. 2.—(a-c) Observed changes in log-odds of nausea by treatment pooling over subjects and attacks.
when migraine pain intensity was moderate or
severe. In the 6 months prior to entering the study,
48%-66% reported moderate or severe nausea,
84%-87% reported moderate or severe photophobia,
and 77%-78% reported moderate or severe
phonophobia.
Model 1: Overall Nausea.—The observed logodds of pre-dose nausea were similar in the AVP825 and oral sumatriptan (see Fig. 2a). However, the
change in nausea over time for attacks treated with
AVP-825 appeared nonlinear, decreasing faster at
earlier time points and then slowly decelerating as
time approached 2 hours. For oral sumatriptan, nausea decreased in a linear fashion from pre-dose
through 2 hours post-treatment.
Consistent with the observed data shown in
Figure 2a, change in nausea was modeled using a
quadratic time trend. Table 2 shows the full set of
results for the Overall Nausea model. There was
significant between subject and between attack variability in nausea (P < .0001 for both random effect
variances). Almost one-half of the total variability
in nausea was between person, nearly one-third was
between attacks (within person), and just under
20% was within attacks. Examining the fixed effects
showed a significant treatment-by-time interaction,
which indicated that an individual experienced a
more rapid decline in their odds of nausea earlier
during an attack when treating with AVP-825 compared to oral sumatriptan; v2(2) 5 34.67, P < .0001.
This was demonstrated by significantly faster IROCs,
where a subject’s nausea risk decreased at a greater
rate for AVP-825 relative to oral sumatriptan at 10
minutes through 60 minutes (P <. 05 for all) (Fig. 3a
and Table 3). It was not until 90 minutes that the two
treatments had similar rates of change over time. By
2 hours, oral sumatriptan was decreasing at a significantly faster rate compared to AVP-825 (P < .05).
Table 4 shows the model-implied treatment differences in nausea odds at each fixed time-point
from pre-dose through 2 hours. Paralleling the findings regarding change in nausea over time, an individual’s odds of nausea during a typical attack were
significantly reduced at all time-points from 30
minutes through 2 hours following treatment
with AVP-825 vs oral sumatriptan (P < .05 for all
0.35
0.17
0.60
0.52
0.02
0.43
0.19
0.02
0.004
0.02
0.005
1.17
0.46
3.38
20.07
21.59
20.31
20.01
0.16
20.81
20.29
0.005
20.14
0.02
8.67
5.57
SE
8096.78
8122.78
8169.02
7.43
12.11
29.56
20.41
22.63
20.60
20.84
0.37
24.21
217.98
1.34
25.62
3.89
-
Test stat.
<.0001
<.0001
<.0001
.68
.009
.55
.40
.71
<.0001
<.0001
.18
<.0001
.0001
-
P
2.85
6.10
24.58
20.37
20.88
20.39
20.01
0.64
21.07
0.09
20.08
0.006
20.33
0.05
0.0006
Est.
.67
1.02
0.39
0.27
0.54
0.47
0.02
0.39
0.31
0.05
0.02
0.003
0.08
0.02
0.004
SE
2533.81
2563.81
2615.51
4.28
5.99
211.81
21.35
21.63
20.84
20.61
1.66
23.42
1.88
24.99
2.40
23.88
1.82
0.13
Test stat.
<.0001
<.0001
<.0001
.18
.10
.40
.54
.10
.0006
.06
<.0001
.02
.0001
.07
.89
P
Model 2: Treatment Emergent Nausea
9.39
4.91
2.79
0.36
21.13
20.87
20.02
0.67
20.57
21.58
0.15
20.006
-
Est.
1.66
0.65
0.46
0.26
0.86
0.70
0.02
0.57
0.26
0.14
0.03
0.002
-
SE
2985.84
3009.84
3047.26
5.66
7.55
6.03
1.39
21.31
21.24
20.93
1.16
22.18
211.65
4.90
22.97
-
Test stat.
Model 3: Nausea Relief
<.0001
<.0001
<.0001
.16
.19
.22
.35
.24
.03
<.0001
<.0001
.003
-
P
Est. 5 Estimate; SE=Standard Error; 22LL 5 22 Log Likelihood; AIC 5 Akaike information criterion; BIC 5 Bayesian information criterion. Reference coding was used
for categorical predictors. Age is centered at 40 years old (Age 5 Age-40) and time is centered at 45 minutes and divided by 10 ([Time – 45]/10). For the fixed effects
(top portion of the table), the test statistics were t values and, for the random effects (bottom portion), the test statistics were z values. For Model 1, the intercept has
df 5 254 and other effects had df 5 11,648. For Model 2, the intercept has df 5 227 and other effects had df 5 6584. For Model 3, the intercept has df 5 162 and other
effects had df 5 3334.
Fixed Effects
Intercept
Period 2 (ref 5 Period 1)
Male (ref 5 Female)
Minority (ref 5 White)
Age
Sequence 1 (ref 5 Seq. 2)
AVP-825 (ref 5 Oral Suma)
Time
Time2 (squared)
Time3 (cubed)
AVP-825 3 Time
AVP-825 3 Time2 (squared)
AVP-825 3 Time3 (cubed)
Random Effects
Subject variance
Attack variance
Model Fit Statistics
22LL
AIC
BIC
Est.
Model 1: Overall Nausea
Table 2.—Parameter Estimates, Standard Errors, Test Statistics, and P-Values for the Fitted Nausea Models
8
Month 2017
Headache
9
a: Overall Nausea
1
0.5
IROC
0.5
IROC
b: Treatment Emergent Nausea
1
0
0
-0.5
-0.5
-1
-1
0
10
10 20 30 40 50 60 70 80 90 100 110 120
20
30
40
Oral Sumatriptan
50
60
70
80
90 100 110 120
Time
Time
Oral Sumatriptan
AVP-825
AVP-825
Fig. 3.—(a,b) Treatment differences in IROCs. More negative IROC values on the y-axis indicate greater reductions (or slower
increases) in nausea at that specific time-point; thus, lower values are better. For “Overall Nausea,” IROCs were significantly
smaller at each time-point from 10 minutes through 60 minutes using AVP-825 compared to oral sumatriptan. For TEN, IROCs
were significantly smaller at all time-points from 10 minutes through 45 minutes using AVP-825, and the treatment differences at
90 and 120 minutes were not statistically significant. Key: Smaller values are better. IROC 5 instantaneous rate of change.
time-points). The odds of nausea were not significantly different from pre-dose through 15 minutes
between treatments (P > .05). Thus, treating with
AVP-825 produced faster IROCs earlier on, which
led to significant treatment differences over time in
odds of nausea at the fixed time-points compared
to oral sumatriptan.
Model 2: Treatment Emergent Nausea.—Figure 2b
shows a plot of the observed TEN data over time stratified by treatment. TEN changed in a nonlinear fashion
for both AVP-825 and oral sumatriptan, but the course
of change differed. AVP-825 appeared to change in a
cubic manner, with TEN increasing earlier (10-30
minutes) followed by reduction (30-60 minutes) and
ultimately leveling out at a low level (60-120 minutes).
However, the longitudinal change in TEN for attacks
treated with oral sumatriptan had a more quadratic
form, increasing through the first hour and decreasing
through the second hour. Figure 2b shows that the
odds of nausea in the first hour decreased for AVP-825
while oral sumatriptan increased. It was not until 2
hours post-dose that the treatments began to show
more comparable levels of nausea.
Results from the three-level TEN multilevel
model (Table 2) showed significant between subject
and between attack variability (P < .0001). About
Table 3.—Model-Implied Treatment Differences in Instantaneous Rates of Change (IROC) in Nausea
Model 1: Overall Nausea
BL
10 minutes
15 minutes
30 minutes
45 minutes
60 minutes
90 minutes
120 minutes
Model 2: Treatment Emergent Nausea
Oral Suma
IROC Est.
AVP-825
IROC Est.
t value
P value
Oral Suma
IROC Est.
AVP-825
IROC Est.
t value
P value
20.33
20.32
20.32
20.30
20.29
20.27
20.24
20.21
20.66
20.61
20.58
20.50
20.42
20.34
20.19
20.03
25.12
25.30
25.40
25.74
25.62
23.23
1.27
2.47
<.0001
<.0001
<.0001
<.0001
<.0001
.001
.20
.01
0.89
0.75
0.38
0.09
20.11
20.26
20.07
0.26
0.16
20.08
20.23
20.30
20.14
0.37
22.29
22.74
25.24
23.88
21.72
1.55
1.33
.02
.006
<.0001
.0001
.09
.12
.18
IROC 5 instantaneous rate of change. More negative IROC estimates implies that nausea is decreasing at faster rate (or
increasing at a slower rate) at that point in time (eg, better outcome). For Model 1, the df for all statistical tests were 11,648.
For Model 2, the df for all statistical tests were 6584. Model 3 is not listed because the treatment-by-time interaction was not
statistically significant.
10
Month 2017
Table 4.—Model-Implied Treatment Differences in Odds of Nausea at Each Time-Point
Model 1: Overall Nausea
BL
10 minutes
15 minutes
30 minutes
45 minutes
60 minutes
90 minutes
120 minutes
Model 2: Treatment Emergent Nausea
OR
95% CI
t value
P value
OR
95% CI
t value
P value
1.27
0.93
0.81
0.57
0.45
0.38
0.37
0.53
0.87-1.86
0.66-1.32
0.58-1.14
0.41-0.81
0.31-0.65
0.26-0.57
0.25-0.56
0.30-0.94
1.23
20.39
21.2
23.12
24.21
24.79
24.67
22.16
.22
.70
.23
.002
<.0001
<.0001
<.0001
.03
1.85
1.37
0.62
0.34
0.23
0.21
0.48
0.89-3.82
0.73-2.54
0.34-1.14
0.19-0.63
0.12-0.44
0.09-0.47
0.19-1.18
1.66
0.98
21.53
23.42
24.56
23.73
21.60
.10
.33
.13
.0006
<.0001
.0002
.11
OR 5 odds ratio. Odds ratios less than 1 indicate that AVP-825 was associated with reduced odds of being nauseous compared
to oral sumatriptan (better outcome). For Model 1, the df for all statistical tests were 11,648. For Model 2, the df for all statistical tests were 6584. Model 3 is not listed because the treatment-by-time interaction was not statistically significant. The
model-implied odds ratio was 0.57 in favor AVP-825 across all time-points.
one-quarter of the total variance in TEN was
between person, one-half was attributable to differences between attacks, and the remainder (25%)
was due to within attack differences. The significant
variance components demonstrated that TEN
varied not only across individuals but also within
individuals, across attacks. Consistent with the
observed data plot in Figure 2b, there was also a significant treatment-by-time interaction, which indicated that change in nausea over time differed
across treatments, v2(3) 5 35.64, P < .0001. Examination of IROC helps show the nature of treatment
differences in longitudinal change in TEN (Fig. 3b
and Table 3). Most notably, an individual’s propensity for TEN was increasing at a significantly faster
rate with oral sumatriptan compared to AVP-825 at
10, 15, 30, and 45 minutes (P < .05 for all). Further,
at 30 and 45 minutes the odds of experiencing nausea were still increasing for oral sumatriptan, but
they were decreasing for AVP-825. From 60 minutes
to 2 hours, TEN was changing in a comparable fashion across both treatment groups (P > .05).
Table 4 shows that there were treatment differences in an individual’s overall odds of nausea at
several time-points. Specifically, from 45 minutes
through 90 minutes, an individual had significantly
lower odds of TEN when treating an attack with
AVP-825 compared to oral sumatriptan (P < .05 for
all). There were no significant treatment differences
in odds of TEN during the first 30 minutes and at
the 2 hour assessment (P > .05 for all).
Model 3: Nausea Relief.—The observed data suggested that AVP-825 had a constant level difference in nausea from 10 minutes through 2 hours for
attacks with pre-dose nausea (Fig. 2c). However,
there did not appear to be treatment differences in
the rate of change in nausea over time (the lines
run parallel).
In Model 3, longitudinal change in Nausea
Relief was modeled using a cubic time trend and
demonstrated significant between subject and
between attack (within subject) variability in nausea (P < .0001), with more than half of the total
variability in nausea being attributable to between
subject differences compared to just over onequarter being due to between attack (within subject) differences. As expected from the observed
data, the treatment-by-time interaction was not statistically significant, v2(3) 5 2.40, P 5 .49. This suggested that the change in nausea over time was
comparable for AVP-825 and oral sumatriptan. For
parsimony, the treatment-by-time interaction terms
were dropped for the final model displayed in
Table 2. Although there were not significant
Headache
treatment differences in the rate of change in nausea over time, in individuals treating an attack with
AVP-825, the odds of experiencing nausea were
reduced by 43% from 10 minutes through 2 hours
(OR 5 0.57, P < .05).
These three statistical models demonstrated
that an individual’s nausea risk differed by treatment. All three models showed that an individual’s
odds of nausea (Overall, TEN, and Nausea Relief)
were significantly lower at several time-points in the
first 2 hours post-dose. Further, for Overall Nausea
and TEN, rates of change in nausea over time differed significantly, with the more favorable longitudinal trends produced when attacks were treated
with AVP-825 compared to oral sumatriptan.
DISCUSSION
We evaluated how nausea unfolds over time
across multiple attacks treated with AVP-825 vs
oral sumatriptan in a multi-attack, crossover study.
We first examined the time course of nausea
following treatment in the overall sample, independent of nausea status at baseline. Next, we examined TEN in attacks free of nausea at baseline.
Finally, we examined relief of nausea in those
attacks that had nausea at baseline. We will consider these results one at a time.
In the overall sample, nausea declined more
rapidly with AVP-825 than with oral sumatriptan.
There was faster instantaneous rate of decline over
the first hour post-treatment with AVP-825. When
not stratifying by baseline nausea status, attacks
treated with AVP-825 showed greater reductions in
nausea than attacks treated with oral sumatriptan.
Unlike most studies, the present report involved
multiple attacks for each person with each treatment. Thus, we can partition the total nausea variance into between and within person components.
We estimated that person to person variation
accounted for about half of the total variation in
nausea. Whereas between-attack variation within
individuals accounted for about one-third of the
total variation and just under 20% of the total variability in nausea was attributed to within attack differences. This means that the nausea trajectories
were influenced by both within and between person
11
factors. While many prior reports show that triptans
effectively relieve nausea, we are not aware of studies able to partition the total nausea variance in a
multiple attack context.14
Next, we found that rates of TEN were higher
with oral sumatriptan than with AVP-825. TEN trajectories for AVP-825 increased slightly through
the first 15 minutes post-dose then decreased for
the next hour (negative IROCs from 30 through 90
minutes). Sumatriptan tablets were associated with
a more prolonged increase in odds of TEN, which
lasted through the first 45 minutes and did not start
to decline until 60 minutes following treatment.
However, because there was no placebo treatment
arm for comparison, it is not known whether this
difference is due to the fact that AVP-825 treats
the nausea associated with a developing migraine
better than oral sumatriptan, or that oral sumatriptan increases TEN through a direct effect on the
gut. Just under one-quarter of the total variation in
TEN status was attributed to between person differences, about half was due to between attack differences, and the remainder (25%) was associated
with within attack differences.
Rates of TEN following oral sumatriptan
100 mg have rarely been studied. The rate of TEN
was 20% for sumatriptan 100 mg vs 12% for placebo
treated subjects in a published post hoc analysis.13
The authors suggested that oral sumatriptan may
cause TEN through a direct effect on the gut. This
effect is biologically plausible as sumatriptan is a sulfonamide, a medication class known to irritate the
gut.17 Bigal et al examined the effect of a sumatriptan cutaneous patch and showed that it did not
cause TEN.18 Similarly, there is no evidence that
injectable sumatriptan causes TEN.15 Combining
results from these studies, we suggest that oral sumatriptan tablets may cause TEN while sumatriptan
administered through non-oral routes does not.
Finally, the third model tested profiles of Nausea Relief only in persons who had it at baseline.
Findings showed that nausea improved following
either of the two treatments, but did not result in
different rates of change over time (ie, similar nausea trajectories across treatments). However, there
was a difference in overall level, suggesting that an
12
individual’s odds of experiencing nausea were consistently reduced through 2 hours with AVP-825
compared to oral sumatriptan.
We have shown advantages of using multilevel
modeling to estimate nausea trajectories. The models disaggregated nausea variability based on a
three-level nesting structure that is reflective of the
real world: repeated measures (level 1) nested
within attacks (level 2) nested within persons (level
3). Further, these models revealed information that
might not otherwise be apparent. Results provided
insights on both the relative speed (eg, Is an individual’s nausea risk decreasing faster using Treatment A or B over time?) and level (eg, At 60
minutes, are an individual’s odds for experiencing
nausea elevated when treating an attack with Treatment A compared to B?) differences across treatments. Taken together, these models are well
suited to test clinical theory and produce insights
that are directly applicable to practice.
This study has several limitations. The COMPASS study did not include a placebo arm, so we do
not have a contemporaneous control group with
which to make contrasts. However, in a multiple
attack, crossover study it might be difficult or even
unethical to ask participants to treat up to five
attacks with placebo. In addition, repeated placebo
administration might attenuate participation even in
the arms where active treatment is offered. When we
partition attacks into those without nausea at baseline (model 2) and with nausea at baseline (model 3)
the sample size in terms of persons and attacks are
reduced with consequent reductions in statistical
power. These reductions may impact the precision of
our estimates, especially the random effects variance
components. However, based on the model performance, the latter did not appear problematic.
The results of this study combined with previous
research may help clinicians optimize migraine treatment. Oral sumatriptan causes TEN while non-oral
sumatriptan, whether administered by injection, cutaneous patch, or breath-powered intra-nasal delivery
appears less likely to cause TEN. Results showed
that nausea risk varied substantially across subjects
and attacks. Future studies should investigate potential attack-level and subject-level covariates that may
Month 2017
help explain this variation. Future research should
also investigate how other migraine-related symptoms develop and resolve over time in conjunction
with nausea. It would be of interest to evaluate the
sequential unfolding of relief of pain, migrainerelated disability, and associated symptoms of
migraine. That work may provide insight into the
mechanisms through which triptans relieve the
broader set of symptoms that define migraine.
Acknowledgments: Authors would like to thank the
COMPASS Study Site Primary Investigators: Roger
Cady, MD, Andrew Cutler, MD, Marshall Freeman,
MD, Gordon Gilson, MD, Jerome Goldstein, MD
Rashmi Halker Singh, MD, Judith Kirstein, MD,
David Kudrow, MD, Peter McAllister, MD, Laszlo
Mechtler, MD, John Rubino, MD, Joel Saper, MD,
Stephen Silberstein, MD, Timothy Smith, MD, Egilius
Spierings, MD, PhD, Cynthia Strout, MD, Stewart
Tepper, MD, Jonathan Wilson, MD, Alan Kravitz,
MD, and Paul Winner, MD. The authors would like to
thank Prescott Medical Communications Group, Chicago, IL, and Emmanuelle Hugentobler, MD, for editorial and administrative support.
STATEMENT OF AUTHORSHIP
Category 1
(a) Conception and Design
Richard B. Lipton, James S. McGinley,
neth J. Shulman, Stephen D. Silberstein,
Wirth, Dawn C. Buse
(b) Acquisition of Data
Kenneth J. Shulman
(c) Analysis and Interpretation of Data
Richard B. Lipton, James S. McGinley,
neth J. Shulman, Stephen D. Silberstein,
Wirth, Dawn C. Buse
KenR. J.
KenR. J.
Category 2
(a) Drafting the Manuscript
Richard B. Lipton, James S. McGinley, Kenneth J. Shulman, R. J. Wirth, Dawn C. Buse
(b) Revising It for Intellectual Content
Richard B. Lipton, James S. McGinley, Kenneth J. Shulman, Stephen D. Silberstein, R. J.
Wirth, Dawn C. Buse
Headache
13
Category 3
(a) Final Approval of the Completed Manuscript
Richard B. Lipton, James S. McGinley, Kenneth J. Shulman, Stephen D. Silberstein, R. J.
Wirth, Dawn C. Buse
12.
13.
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