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Original Article
Comparison of frovatriptan plus
dexketoprofen (25 mg or 37.5 mg) with
frovatriptan alone in the treatment of
migraine attacks with or without aura:
A randomized study
Vincenzo Tullo
1
, Fabio Valguarnera
2
, Piero Barbanti
3
,
Pietro Cortelli
4
, Giuliano Sette
5
, Gianni Allais
6
,
Florindo d’Onofrio
7
, Marcella Curone
1
, Dario Zava
8
,
Deborha Pezzola
8
, Chiara Benedetto
6
, Fabio Frediani
9
and Gennaro Bussone
1
Abstract
Background: Drugs for migraine attacks include triptans and NSAIDs; their combination could provide greater symptom
relief.
Methods: A total of 314 subjects with history of migraine, with or without aura, were randomized to frovatriptan 2.5 mg
alone (Frova), frovatriptan 2.5 mg þdexketoprofen 25 mg (FroDex25) or frovatriptan 2.5 mg þdexketoprofen 37.5 mg
(FroDex37.5) and treated at least one migraine attack. This was a multicenter, randomized, double-blind, parallel-group
study. The primary end point was the proportion of pain free (PF) at two hours. Secondary end points were PF at one
and four hours, pain relief (PR) at one, two, four hours, sustained PF (SPF) at 24 and 48 hours, recurrence at 48 hours,
resolution of nausea, photophobia and phonophobia at two and four hours, the use of rescue medication and the
judgment of the treatment.
Results: The results were assessed in the full analysis set (FAS) population, which included all subjects randomized and
treated for whom at least one post-dose intensity of headache was recorded.
The proportions of subjects PF at two hours (primary end point) were 29% (27/93) with Frova compared with 51%
(48/95 FroDex25 and 46/91 FroDex37.5) with each combination therapies (p<0.05). Proportions of SPF at 24 hours
were 24% (22/93) for Frova, 43% (41/95) for FroDex25 (p<0.001) and 42% (38/91) for FroDex37.5 (p<0.05). SPF at
48 hours was 23% (21/93) with Frova, 36% (34/95) with FroDex25 and 33% (30/91) with FroDex37.5 (p¼NS).
Recurrence was similar for Frova (22%, 6/27), FroDex25 (29%, 14/48) and FroDex37.5 (28%, 13/46) (p¼NS), meaning
a lack of improvement with the combination therapy.
Statistical adjustment for multiple comparisons was not performed.
No statistically significant differences were reported in the occurrence of total and drug-related adverse events.
FroDex25 and FroDex37.5 showed a similar efficacy both for primary and secondary end points. There did not seem
to be a dose response curve for the addition of dexketoprofen.
Conclusion: FroDex improved initial efficacy at two hours compared to Frova whilst maintaining efficacy at 48 hours in this
study. Tolerability profiles were comparable. Intrinsic pharmacokinetic properties of the two single drugs contribute to
this improved efficacy profile.
1
Department of Clinical Neuroscience, National Neurological Institute
Carlo Besta, Italy
2
Sestri Ponente Hospital ‘‘Padre Antero Micone’’, Italy
3
Unit for treatment and research of headaches and pain, IRCCS San
Raffaele Pisana, Italy
4
Neurological Clinic, Department of Neurological Science, University of
Bologna, Italy
5
Sant’Andrea Hospital, Italy
6
Department of Gynecology and Obstetrics, Women’s Headache Center,
University of Turin, Italy
7
San Giuseppe Moscati Hospital, Italy
8
Istituto Luso Farmaco d’Italia, Peschiera Borromeo, Italy
9
Ospedale S. Carlo Borromeo, Italy
Corresponding author:
Vincenzo Tullo, Department of Clinical Neuroscience, National
Neurological Institute Carlo Besta, Via Celoria 11, 20133 Milano, Italy.
Email: vintullo@tin.it
Cephalalgia
2014, Vol. 34(6) 434–445
!International Headache Society 2013
Reprints and permissions:
sagepub.co.uk/journalsPermissions.nav
DOI: 10.1177/0333102413515342
cep.sagepub.com
Keywords
Frovatriptan, dexketoprofen, migraine attacks, triptans, NSAIDs
Date received: 25 June 2013; revised: 6 August 2013; 13 September 2013; 7 October 2013; accepted: 11 October 2013
Introduction
Migraine affects approximately 18% of women and
6% of men in Western countries (1). The prevalence
peaks in subjects between 25 and 55 years old. The
burden of migraine is enormous; in the United
States (US) migraine sufferers spend a total of 112 mil-
lion days bedridden and the annual cost of missed
work or reduced productivity is $5.6 billion to $17.2
billion (1,2).
The International Headache Society (IHS) criteria
for diagnosing migraine (3) are the most widely used
diagnostic criteria around the world. Drugs effective for
treating migraine attacks include triptans, analgesics
(such as nonsteroidal inflammatory drugs (NSAIDs)),
ergot derivatives and antiemetics (4). Triptans, mar-
keted in the early 1990s, were a major advance in the
treatment of moderate-severe acute migraine attacks
(4). They are selective 5-HT1
B/D
agonists. Seven trip-
tans are available, being, theoretically, similar, but
patients note differences in effectiveness and in toler-
ance (5).
Frovatriptan is one of the newest triptans and its
distinct pharmacokinetic and pharmacodynamics pro-
file means that it has the clinical potential for a long
duration of action and a low likelihood of side effects
and drug interactions (6). The elimination half-life of
frovatriptan is five times that of other triptans, while
the time to maximum concentration (t
max
) is similar to
other triptans when given orally (5,7–10).
NSAIDs and other simple analgesics are indicated
for the treatment of mild or moderate migraine attacks
(4). Dexketoprofen works by blocking the action of
cyclooxygenase (COX), which is involved in the pro-
duction of prostaglandins, and thereby reduces inflam-
mation and pain (11,12). Dexketoprofen maximum
plasma concentrations are observed around 30 minutes
after an oral dose. Its elimination half-life, however, is
quite short (13). Dexketoprofen proved to be effective
and very fast in reducing pain intensity and accom-
panying symptoms in 42 women affected by migraine
with or without aura (14).
The complexity of the pathophysiology of
migraine partially explains why none of the cur-
rently available monotherapies provides broad cover-
age of the multiple pathogenic processes in migraine
(15–25).
A therapy that targets multiple mechanisms may
confer advantages over monotherapy, and triptans
and NSAIDs target distinct aspects of the vascular
and inflammatory processes hypothesized to underlie
migraine. This possibility is supported by the results
of several clinical studies, including those on the con-
comitant use of sumatriptan succinate with naproxen
sodium and rizatriptan with rofecoxib (26–30).
The rationale for combining dexketoprofen with fro-
vatriptan is linked to the intrinsic pharmacokinetic
properties of the two drugs; dexketoprofen is absorbed
rapidly and contributes to the early efficacy of the com-
bination, whereas frovatriptan persists longer and so
provides sustained efficacy with less recurrence.
The aims of this study were to evaluate the efficacy
and tolerability of the combination therapy frovatrip-
tan plus dexketoprofen over frovatriptan alone in the
acute treatment of migraine attacks.
Methods
Study population
The study recruited subjects of male or female gender,
18–65 years old, with a current history of migraine with
or without aura, according to IHS 2004 criteria, and
with at least one but no more than six migraine attacks
per month for six months prior to entering the study.
Figure 1 shows the study flowchart.
Patients could not be enrolled in the study if they:
(a) had coronary artery or cerebrovascular disease; (b)
had uncontrolled hypertension; (c) had other types of
headache in addition to migraine with or without aura;
(d) were taking ergotamine (or its derivatives),
St John’s Wort (Hypericum perforatum), monoamine
oxidase (MAO)-inhibitors, NSAIDs (COX-2 inhibi-
tors), oral corticosteroids, warfarin or other coumarins,
selective serotonin reuptake inhibitors, or anti-
aggregant agents such as aspirin, heparin, lithium,
methotrexate, hydantoins and sulphonamides; (e) had
severe liver or renal impairment; (f) had a history of
alcohol, analgesic or psychotropic drug abuse; (g) had
known hypersensitivity to either of the study drugs or
to any other NSAIDs; (h) had active peptic ulcer/bleed-
ing or a history of gastrointestinal bleeding or perfor-
ation related to NSAID therapies; (i) had bronchial
asthma; (j) were pregnant or breast feeding.
Tullo et al. 435
Written informed consent was obtained from all
patients prior to their inclusion in the study.
The study was approved by the independent institu-
tional review boards of the centers in which the study
was carried out. The study was conducted according to
the Declaration of Helsinki and Good Clinical Practice
and was registered internationally (Eudract number
2009-011577-32).
PATIENTS SCREENED
N = 321
PATIENTS RANDOMIZED
N = 314
PATIENTS ASSIGNED
TO GROUP:
Frovatriptan
N = 106
PATIENTS ASSIGNED
TO GROUP:
F + DXP 37.5 mg
N= 103
COMPLETED
N = 106
PP Population
N = 67
PP Population
N = 64
Exclusion from FAS Population:
- No attacks treated (N = 12)
- Lack of efficacy data (N=1)
Exclusion from PP Population:
- Prohibited treatments (N =2)
- Inconsistency diaries (N=22)
- Informed consent’s date not consistent
(N=1)
- Migraine attack after 30 days (=1)
- Prohibited treatments+Migraine attack
after 30 days (=1)
- Prohibited treats+Diaries (N =3)
- Wrong visit interval+Diaries (N=1)
PATIENTS ASSIGNED
TO GROUP:
F + DXP 25 mg
N= 105
- Violation of selection criteria (N = 2)
- Other (N = 5)
COMPLETED
N = 105
COMPLETED
N = 103
FAS Population
N = 93
Exclusion from FAS Population:
- No attacks treated (N = 10)
Exclusion from FAS Population:
- No attacks treated (N = 11)
- Lack of efficacy data (N=1)
PP Population
N = 71
Exclusion from PP Population:
- Prohibited treatments (N =4)
- Inconsistency diaries (N=18)
- Prohibited treatments+Diaries (N =1)
- Lab test after V0+Diaries (N=1)
- Prohibited treatments+wrong visit
interval (N =2)
Exclusion from PP Population:
- Protocol criteria violation (N = 1)
- Prohibited treatments (N =2)
- Inconsistency di aries (N=13)
- Informed consent’s date not
consistent (N=1)
- Prohibited treats+Diaries (N =2)
- Wrong visit interval+Diaries
(N=1)
FAS Population
N = 95
FAS Population
N = 91
Figure 1. Flow diagram of participants throughout the study.
FAS: full analysis set; PP: per protocol; F: frovatriptan; DXP: dexketoprofen.
436 Cephalalgia 34(6)
Study design
This was a multicenter, randomized, double-blind,
active-controlled, three parallel-group, phase 3 study
performed in 25 Italian centers from July 2009 to April
2010. Over-encapsulation was used to ensure blinding.
This active treatment dose-comparison concurrent
control study compared frovatriptan 2.5 mg þ
dexketoprofen 25 mg (FroDex25) or frovatriptan
2.5 mg þdexketoprofen 37.5 mg (FroDex37.5) to frova-
triptan 2.5 mg þplacebo (Frova), in acute treatment of
migraine with or without aura attacks in three parallel
groups of 100 subjects each. The study protocol also
foresaw a comparison between FroDex25 and
FroDex37.5.
After the screening visit, subjects were assigned by
the investigators to one of the three treatment groups
using randomization lists prepared by InnoPharma
s.r.l. generated using three-subject blocks to balance
the treatments. The lists were provided to all sites
before the start of the study. Code-break envelopes
were provided to the sites and could be opened in the
case of an emergency. To keep the patients and study
investigators blind to the treatment, the study drugs
were over-encapsulated.
Frovatriptan, dexketoprofen and placebo tablets
were over-encapsulated in capsules suitable to keep
the blinding. Two colors of capsules were used: white
and red. The extemporary combination of frovatriptan
2.5 mg þdexketoprofen 37.5 mg, frovatriptan 2.5 mg þ
dexketoprofen 25 mg, frovatriptan 2.5 mg þplacebo
was provided in indistinguishable carton boxes identi-
fied by the randomization numbers, each containing
one treatment dose blister with two capsules: a red
and a white one.
All study end point parameters were recorded in a
personal diary and, for the intensity of the headache
attack, a four-point rating scale recommended by the
IHS (0 ¼no headache, 1 ¼mild headache, 2 ¼moderate
headache, 3 ¼severe headache) was used. Similar scales
were used for assessment of the associated symptoms
(nausea, photophobia and phonophobia).
The active controlled design was chosen in accord-
ance with guidelines on the choice of control groups in
studies aimed at demonstrating superiority of a new
treatment when an established treatment already
exists (3,4). The two doses of 25 mg and 37.5 mg of
dexketoprofen were chosen based on available litera-
ture data, and on the results from previous pre-clinical
and clinical studies (12). The frovatriptan dose of
2.5 mg is the dose recommended in the SmPC (31).
During the randomization visit, after signing written
informed consent, subjects provided their clinical,
medication and migraine history. Physical and neuro-
logical examinations and a pregnancy test (if appropri-
ate) were performed. Blood pressure and heart rate
were measured for all subjects. The degree of
migraine-associated disability was also determined,
using the Migraine Disability Assessment (MIDAS)
questionnaire. At the end of the visit a headache
diary was dispensed with the study medication in
order to document the characteristics of the headache
pain and associated symptoms, and subjects were
instructed to take the study medication and complete
the diary for the first migraine attack that occurred
during the study period (i.e. within one month from
randomization).
The study treatment was self-administered orally in
single administration as early as possible after the onset
of the migraine headache. During the study, three visits
to the clinical center were scheduled: one at the screen-
ing, one at the randomization visit and a follow-up visit
between 72 hours and 14 days (2) after the migraine
attack.
Data analysis
The primary efficacy variable to assess the possible
superiority of frovatriptan plus dexketoprofen (high
and low doses) over frovatriptan alone was the percent-
age of subjects pain free at two hours before any rescue
medication. A minimum difference of 20% in the pro-
portion of patients who were pain free was considered
evidence of the clinical superiority of frovatriptan plus
dexketoprofen (high dose) over frovatriptan alone.
The 20% difference for the power was pre-specified
in the study protocol and was determined by taking
into account that there were not published or unpub-
lished data of FroDex combination therapy versus
Frova monotherapy; there were not specific requests
coming from migraine guidelines for superiority trials
(32). The only available data published of a combin-
ation therapy (SumaNapro) versus monotherapy
(Suma) showed a mean difference within the range of
9% and 15%. For these reasons we considered a 20%
difference a reasonable clinically important difference
to reach (25–27,35). The study’s primary analysis popu-
lation was the full analysis set (FAS) population that
included all subjects randomized and treated for whom
at least one post-dose intensification of headache was
recorded.
The per-protocol (PP) population consisted of all
patients who treated a migraine attack without proto-
col violations. This population was identified prior to
database lock and was used as a confirmatory analysis.
Secondary study end points were:
.Proportion of pain-free subjects at one hour and
four hours, defined as subjects free of pain one
hour and four hours before any rescue medication,
according to IHS guidelines (3);
Tullo et al. 437
.Proportion of patients with headache relief at one,
two and four hours, defined as the percentage of
subjects with a decrease in headache from severe or
moderate to mild or none within one hour,
two hours and four hours, according to IHS guide-
lines (3);
.Sustained pain free, defined as the percentages of
subjects who were pain free within two hours with
no use of rescue medication or recurrence within 24
hours and 48 hours, according to IHS guidelines (3);
.Recurrence, defined according to IHS guidelines as a
headache of any severity returning within 48 hours,
in a subject who was pain free at two hours and who
had not taken any rescue medication (3);
.Proportion of subjects with resolution of nausea,
vomiting, photophobia and phonophobia;
.Proportion of subjects taking rescue medication;
.Time to meaningful relief, defined as a reduction of
at least two points on the four-point scale (i.e. from
severe pain score of 3 at baseline to mild or no pain
of score 1/0);
.Speed of onset at 60, 90, 120 and 240 minutes,
defined as a decrease of one point in pain intensity;
.Subjects’ preference for treatments.
Main and secondary variables were analyzed at a two-
sided significance level of 0.05.
The tolerability analysis was conducted on all ran-
domized patients and included the incidence of adverse
events and changes in vital signs during the study.
Continuous variables were summarized by computing
mean values and their standard deviation (SD), while
categorical variables were summarized by computing
their absolute values and frequencies (as percentages).
The efficacy assessments were made by the patient at
the time of dosing (baseline) and at two, four, 24 and 48
hours after dosing. The data were analyzed using SASÕ
version 9.2.
The planned sample size of 300 randomized subjects
(100 per group) (allowing for a drop-out rate of at least
20%) was chosen to provide the study with the statis-
tical power to detect the possible superiority of the test
drug (FroDex37.5) with respect to the reference treat-
ment (Frova alone), on the percentage of subjects pain
free at two hours before any rescue medication, as the
primary variable, and assuming 20% as the margin of
superiority and a power of almost 90% (88%). Thus,
the test drug was to be considered superior to the ref-
erence one if the difference (test minus reference) in the
primary variable was >20%.
The primary variable was assessed by the Fisher-
Freeman-Halton Exact test statistic using a 3 2 con-
tingency table for tests of association and a 2 2 con-
tingency table for comparisons between treatments. All
other secondary parameters were assessed in the same
way as the primary variable. The level of significance
was set at 0.05 for all analyses. The primary and all
secondary parameters were assessed in the FAS popu-
lation, which included all subjects randomized and trea-
ted for whom at least one post-dose intensification of
headache was recorded.
All pvalues for secondary end points are reported
without adjustment for multiplicity.
Results
A total of 314 patients, of the planned 300, were ran-
domized: 106 in the Frova group, 105 in the
FrovaDex25 group and 103 in the FroDex37.5 group.
Table 1 shows the main demographic and clinical char-
acteristics of the patients in the FAS population. Most
of the subjects enrolled were females. A statistically sig-
nificant difference was found in the gender population
considering the three groups. This difference did not
influence results of the primary end point. There were
no statistically significant differences between the treat-
ment groups in any other demographic or clinical
characteristic.
Primary end point
Overall comparison among treatments showed a statis-
tically significant difference (p¼0.003, Fisher-
Freeman-Halton Exact test). In the FAS population,
the proportion of patients who were pain free at two
hours was 29% (27/93) with Frova, 51% (48/95) for
FroDex25 (odds ratio (OR) ¼2.5 (1.37–4.5), p<0.05)
and also 51% (46/91) for FroDex37.5 (OR ¼2.5 (1.36–
4.6), p<0.05) (Figure 2). There was not a statistically
significant difference in the comparison between
FroDex25 and FroDex37.5 (OR ¼1 (0.56–1.78), p¼1).
Secondary end points
The results of the analysis of secondary end points are
summarized in Table 2.
There was not a statistically significant difference in
the comparison between FroDex25 and FroDex37.5 in
all the secondary end points.
FroDex 25 was better than Frova in nearly all of the
secondary end points. In particular the proportions of
pain free at four hours and of pain relief at one and two
hours were significantly better (p<0.05). Also in terms
of sustained effect, more so at 24 than at 48 hours,
FroDex25 was better than Frova. With respect to
recurrence, however, the results are similar between
the Frova and FroDex25 groups.
FroDex37.5 was significantly better than Frova in
nearly all of the secondary end points, including pain
free at four hours and pain relief at one and two hours.
438 Cephalalgia 34(6)
Table 1. Demographic and clinical data of the 279 patients in the FAS population at the time of randomization. Data are shown
as mean (SD), or absolute (n) and relative frequency (%).
Frovatriptan
(93)
FroDex 25 mg
(95)
FroDex 37.5 mg
(91)
FAS
(279)
All randomized
(314)
PP
(202)
n(%) n(%) n(%) n(%) n(%)
Ages (years) 38.3 9 38.2 10 40 10 38.8 10 38.6 10 39.2 10
Females (n. %) 89 (95) 84 (88)a* 75 (82)a* 248 (89) 272 (87) 178 (88)
Height (cm. mean SD) 164.4 5.8 165.8 17.6 166.4 17.7 165 7.1 166 7.4 166 7.4
Weight (kg. mean SD) 61.1 8.7 61.4 10 63.5 12.1 62 10.4 62.2 10.4 62.3 10.5
MIDAS score (mean SD) 23 16.9 25.6 29.4 23.1 16.6 23.9 21.8 24.3 23.1 25.4 24.1
Presence of aura (n%) 9 (10) 2 (2) 5 (5) 16 (8) 20 (6) 11 (5)
Intensity of attack
Mild (n%) 8 (9) 6 (6) 3 (3) 17 (6) 18 (6) 11 (5)
Moderate (n%) 58 (62) 62 (65) 57 (62) 177 (63) 197 (63) 122 (60)
Severe (n%) 27 ( 29) 27 (28) 31 (34) 85 (31) 99 (32) 69 (34)
Presence of nausea (n%) 45 (48) 47 (49) 42 (46) 134 (48) 149 (48) 95 (47)
Presence of photophobia (n%) 64 (68) 61 (64) 63 (68) 188 (67) 211 (67) 138 (68)
Presence of phonophobia (n%) 58 (62) 62 (65) 53 (58) 173 (62) 194 (62) 129 (64)
Preventive therapy (n%)
Antidepressant 8 (9) 9 (9) 10 (11) 27 (10) 30 (10) 16 (8)
Antiepileptics 7 (8) 6 (6) 10 (11) 23 (8) 25 (8) 15 (7)
Beta- blocking agents 3 (3) 3 (3) 10 (11) 16 (5) 19 (6) 12 (6)
Triptan users (n%) 66 (71) 68 (72) 62 (68) 196 (70) 218 (69) 132 (65)
NSAIDs users (n%) 28 (30) 19 (20) 22 (24) 69 (25) 84 (27) 41 (20)
a
Statistically significant difference (p<0.05) between the group treated with frovatriptan alone and the groups treated with combination therapy.
FAS: full analysis set; FroDex: frovatriptan þdexketoprofen; PP: per protocol. MIDAS: Migraine Disability Assessment; NSAIDs: nonsteroidal anti-
inflammatory drugs.
29%
(27/93)
*
51%
(48/95)
*
51%
(46/91)
0
10
20
30
40
50
60
70
80
90
100
Frova FroDex25 FroDex37.5
Proportion (%)
Figure 2. Proportion (%) of pain free at two hours after administration of Frova, FroDex25 and FroDex37.5 in the 279 patients of
the FAS population. Asterisks indicate a statistically significant difference (p<0.05) between the group treated with frovatriptan alone
and the groups treated with combination therapy.
Frova: frovatriptan 2.5 mg alone; FroDex25: frovatriptan 2.5 mg þdexketoprofen 25 mg; FroDex37.5: frovatriptan 2.5 mg þ
dexketoprofen 37.5 mg; FAS: full analysis set.
Tullo et al. 439
There was also a significant increase in the proportion
of patients who were sustained pain free at 24 hours,
but a nonsignificant increase (from 23% to 33%) in
sustained pain free at 48 hours.
Also in this comparison, the proportion of recur-
rence was similar between Frova and the combin-
ation therapy. The percentages of subjects with
resolution of nausea, photophobia and phonophobia
at one and two hours were higher among patients
taking the combination therapy than among those
receiving Frova monotherapy, reaching statistically
significant difference in most of them, as summarized
in Table 2.
Mean time to meaningful relief was 15.43 16.06 for
Frova, 9.80 13.37 for FroDex25 and 9.70 12.35
hours for FroDex37.5. This difference reached a statis-
tical significance for FroDex25 versus Frova.
The speed of onset was calculated at 60, 90, 120 and
240 minutes. In all time points, the combination ther-
apy was better than monotherapy, reaching a statistic-
ally significant difference at 60, 90 and 120 minutes.
Finally, the treatment was judged excellent or good
by 56% of patients overall (by 44% in the Frova group,
60% in the FroDex25 group and 64% in the
FroDex37.5 group, p<0.05 for both comparisons).
Tolerability
The tolerability analysis was carried out in 281 patients
(FAS population, 279 patients, plus two patients who
didn’t take the drugs in the correct way but were, how-
ever, counted in the tolerability analysis). Total adverse
events were reported by 9 patients during treatment
with Frova, by 18 during treatment with FroDex25
Table 2. Results for the secondary end points of the study.
Frovatriptan
(93)
FroDex25 mg
(95)
Frovatriptan
(93)
FroDex37.5 mg
(91)
n(%) n(%) pn(%) n(%) p
Primary end point
Pain free at two hours 27 (29) 48 (51) <0.05 27 (29) 46 (51) <0.05
Secondary end point
Pain free at one hour 4 (4) 8 (8) 0.372 4 (4) 7 (8) 0.369
Pain free at four hours 44 (47) 62 (65) <0.05 44 (47) 65 (71) <0.001
Pain relief at one hour
a
20 (24) 40 (45) <0.05 20 (24) 35 (40) <0.05
Pain relief at two hours
a
54 (64) 75 (84) <0.05 54 (64) 70 (80) <0.05
Pain relief at four hours
a
73 (86) 81 (91) 0.346 73 (86) 80 (91) 0.347
Sustained pain free at 24 hours 22 (24) 41 (43) <0.05 22 (24) 38 (42) <0.05
Sustained pain free at 48 hours 21 (23) 34 (36) 0.055 21 (23) 30 (33) 0.139
Recurrence 48 hours
b
6 (22) 14 (29) 0.594 6 (22) 13 (28) 0.783
Resolution of nausea at one hour 52 (56) 69 (73) <0.001 52 (56) 69 (76) <0.001
Resolution of nausea at two hours 71 (76) 83 (87) 0.059 71 (76) 80 (88) 0.054
Resolution of photophobia at one hour 39 (42) 56 (59) <0.001 39 (42) 49 (54) 0.139
Resolution of photophobia at two hours 60 (65) 82 (86) <0.001 60 (65) 72 (79) <0.05
Resolution of phonophobia at one hour 50 (54) 59 (62) 0.123 50 (54) 60 (66) 0.1
Resolution of phonophobia at two hours 64 (69) 83 (87) <0.001 64 (69) 76 (84) <0.05
Rescue medication 42 (45) 31 (33) 0.1 42 (45) 26 (29) <0.05
Time to meaningful relief (hours) 15.4 16 9.8 13.4 <0.05 15.4 16 9.7 12.4 0.155
Speed of onset at one hour 31 (33) 52 (55) <0.05 31 (33) 55 (60) <0.001
Speed of onset at 90 minutes 57 (61) 74 (78) <0.05 57 (61) 68 (75) 0.059
Speed of onset at two hours 64 (69) 79 (83) <0.05 64 (69) 78 (86) <0.05
Speed of onset at four hours 81 (87) 88 (93) 0.234 81 (87) 84 (92) 0.333
Treatment good or excellent 41 (44) 57 (60) <0.001 41 (44) 58 (64) <0.001
Analyses were conducted with Fisher’s exact test, except Time to meaningful relief (Log rank, Mantel-Cox). There has been no correction for multiple
comparisons.
a
Pain relief at one, two and four hours was calculated only on moderate-severe migraine, 85, 89, 88 patients in the Frova, FroDex25 and FroDex37.5
group, respectively.
b
Recurrence was calculated on Pain free at two hours. FAS: full analysis set; FroDex: frovatriptan þdexketoprofen. All end points were calculated on
the FAS population.
440 Cephalalgia 34(6)
and by 15 patients during treatment with FroDex37.5
(10%, 19% and 16%, respectively, p¼NS). The
number of total adverse events was 59, (19 with
Frova, 22 for FroDex25 and 18 with FroDex37.5,
p¼NS), most of which were of mild or moderate inten-
sity. There were two serious adverse events (one case of
vestibular neuronitis in the FroDex25 group and one
case of loss of consciousness in the Frodex37.5 group),
neither of which was considered related to the study
treatments.
Drug-related adverse events were reported by 3
patients during treatment with Frova, by 10 during
treatment with FroDex25 and by 5 patients during
treatment with FroDex37.5 (3%, 11% and 16%,
respectively, p¼NS).
The number of drug-related adverse events was 26
(44% of the total events), 9 with Frova, 11 for
FroDex25 and 6 with FroDex37.5, p¼NS (Table 3).
Discussion
In this active treatment dose comparison concurrent
control study, the combination of frovatriptan
2.5 mg þdexketoprofen 25 mg or 37.5 mg showed
better efficacy than frovatriptan alone across a range
of efficacy end points, while maintaining a similar tol-
erability profile. Our results were consistent both for
the FAS and PP populations.
The doses of the two components of the combin-
ation were within the respective approved ranges of
single daily doses recommended for use by adults in
Europe. In fact, the frovatriptan dose is half the max-
imum allowed daily dose (5 mg), while dexketoprofen
25 mg is a third and dexketoprofen 37.5 mg is half of
the maximum allowed daily dose (75 mg) (13,31).
The primary end point of the study was the propor-
tion of subjects who were pain free at two hours with-
out rescue medication. This end point was chosen as
primary because it is recommended by many authorities
as being the most appropriate for assessing the efficacy
of acute migraine treatments in randomized, controlled
trials (3,4,33,34).
The most relevant result of our study is that the pro-
portion of patients who were pain free at two hours was
significantly higher with combination therapy than with
frovatriptan alone and reached more than 50% in the
groups treated with combination therapy, meaning that
for every two patients treated with combination ther-
apy, one was pain free at two hours. The proportion
of pain free obtained with frovatriptan alone in this
study is very similar to those obtained in recently pub-
lished double-blind studies of multiple migraine
attacks (7–10) while the results obtained with the com-
bination therapy are consistent with, or even better
than, those obtained with sumatriptan þnaproxen
sodium (pain free at two hours: 30%–34% with combin-
ation therapy versus 23%–25% with sumatriptan alone,
with a mean difference within the range of 9% and 15%)
(25), although direct comparison studies of the two
combination treatments are lacking.
Among the secondary end points a sustained pain-
free status, the ideal migraine treatment response, is
today considered the hardest end point achievable in
clinical studies and in our study we used the best def-
inition from recent guidelines (3,4,33). In our study the
proportion of sustained pain free patients at 24 hours
was significantly higher with both doses of the combin-
ation therapy than with frovatriptan monotherapy,
42%–43% versus 24%. The proportion of sustained
pain free at 48 hours was also different between the
frovatriptan monotherapy and combination therapy
groups with around a quarter (23%) achieving this end-
point with Frova compared to about a third with
both combination treatments (33% and 36% for the
FroDex25 and FroDex37.5 groups, respectively)
(Figure 3). These differences were not statistically sig-
nificant but it should be remembered that the trial was
not powered for this particular endpoint.
The proportion of sustained pain free with frovatrip-
tan alone is consistent with those obtained in recently
published, double-blind studies (7–10) while results
obtained with combination therapy at 24 hours are in
line with those obtained with sumatriptan þnaproxen
sodium (sustained pain free at 24 hours: 23%–25%
with combination therapy versus 14%–6% with suma-
triptan alone) (25).
As indicated by IHS guidelines, recurrence was
assessed in the time period up to 48 hours, which is a
more stringent end point than recurrence at 24 hours (3).
The proportion of recurrence was similar in the three
groups (Frova 22%, FroDex25 29%, FroDex37.5
28%, p¼0.80). The recurrence findings with frovatrip-
tan alone in our study were in line with the rates in three
recently published head-to-head studies comparing fro-
vatriptan against three different triptans (7–10). The
proportion of recurrence among the patients who took
the combination therapies was similar to the rate in the
group treated with frovatriptan alone. These results are
surprising as one of the aims of the study was to dem-
onstrate a superiority of combination therapy versus
monotherapy in reducing recurrence. One possible
explanation could be that the sustained effect of com-
bination therapy is largely driven by the long half-life of
frovatriptan (31–35) (Figure 3).
Interestingly, the use of rescue medication was lower
in the groups treated with combination therapy
(FroDex25 33%, FroDex37.5 29%) than in the group
treated with Frova (45%). In particular the difference
between the Frova and FroDex37.5 groups was statis-
tically significant (p<0.05): combination therapy
Tullo et al. 441
Table 3. Distribution of absolute numbers of all adverse events and drug-related adverse events between the three treatment
groups in the 281 patients included in the safety analysis.
Frovatriptan (94) FroDex 25 mg (95) FroDex 37.5mg (92)
n(%) n(%) n(%)
Drug related All Drug related All Drug related All
Gastrointestinal disorders – 1 (1) 7 (7) 11 (12) 4 (4) 9 (10)
Abdominal distension – – – – – 1 (1)
Abdominal pain – – 1 (1) 1 (1) – –
Abdominal pain upper – 1 (1) 1 (1) 2 (2) – –
Colitis – – 1 (1) 1 (1) – –
Diarrhea – – – – – 1 (1)
Dry mouth – – 1 (1) 1 (1) – –
Dyspepsia – – 3 (3) 5 (5) – –
Nausea – – – 1 (1) 3 (3) 5 (5)
Retching – – – – – 1 (1)
Vomiting – – – – 1 (1) 1 (1)
General disorders 4 (4) 5 (5) – 1 (1) 1 (1) 1 (1)
Asthenia – – 1 (1) – –
Chest discomfort 1 (1) 1 (1) – – – –
Chills 1 (1) 1 (1) – – – –
Fatigue – – – – 1 (1) 1 (1)
Hyperhidrosis 2 (2) 2 (2) – – – –
Pyrexia – 1 (1) – – – –
Infections and infestations – 1 (1) – 2 (2) – 1 (1)
Cystitis – – – 1 (1) – –
Influenza – – – – – 1 (1)
Nasopharyngitis – 1 (1) – – – –
Vestibular neuronitis (SAE) – – – 1 (1) – –
Musculoskeletal disorders 1 (1) 2 (2) – – – 1 (1)
Musculoskeletal chest pain 1 (1) 1 (1) – – – –
Pain in extremity – 1 (1) – – – 1 (1)
Nervous system disorders 3 (3) 8 (9) 3 (3) 5 (5) – 4 (4)
Agitation 1 (1) 1 (1) – – – –
Dizziness 1 (1) 2 (2) – – – –
Head discomfort – – 1 (1) 1 (1) – 1 (1)
Hyperesthesia – 1 (1) – – – –
Loss of consciousness (SAE) – – – – – 1 (1)
Migraine – 1 (1) – 1 (1) – –
Paresthesia – – 1 (1) 1 (1) – –
Photophobia – 1 (1) – – – –
Nervousness – – – – – 1 (1)
Somnolence – – 1 (1) 2 (2) – –
Tremor 1 (1) 1 (1) – – – –
Vertigo – 1 (1) – – – 1 (1)
Polyuria 1 (1) 1 (1) – – – –
Dysmenorrhea – 1 (1) – 1 (1) – 1 (1)
Epistaxis – – 1 (1) 1 (1) – –
Erythema – – – 1 (1) – –
(continued)
442 Cephalalgia 34(6)
demonstrated both a more immediate and a more sus-
tained effect over 24 hours versus monotherapy; this is
probably the reason why patients taking combination
therapy needed to take less rescue medication. All the
study treatments were well tolerated with no safety con-
cerns identified in this study. The number of treatment-
related adverse events was low and the type of events
reported were similar to those previously described for
the two active ingredients. It is important to underline
that in this study population the higher dose of the com-
bination therapy (frovatriptan 2.5 mg þdexketoprofen
37.5 mg) showed a similar efficacy, not statistically sig-
nificant, both for primary and secondary end points.
This lack of dose response seen with the two doses of
FroDex could be explained by a ceiling effect that
occurs when adding an NSAID (dexketoprofen) to a
triptan (frovatriptan).
The results of this study should be interpreted in the
context of its limitations. First of all, as in the study
by Brandes et al. (25), the patients’ most common
pre-study migraine medications were NSAIDs and trip-
tans. These are the most common medications taken by
migraineurs generally. The degree to which the efficacy
data from this study can be extrapolated to NSAID-
and triptan-naı
¨ve patients and to patients with migraine
refractory to these kinds of drugs is unknown (21).
A second limitation is that the tablets of frovatriptan,
dexketoprofen and placebo were over-encapsulated
separately. The over-encapsulation could decrease the
speed of absorption of the drug during a migraine
attack. Moreover, we did not compare FroDex with
frovatriptan and dexketoprofen taken together as a
unique tablet, but for patients for whom adherence to
taking two pills is an issue, the combination pill would
have obvious advantages.
Our study did not include a dexketoprofen alone arm,
but we must underline that the purpose of developing a
combination therapy is to maximize both the proportion
of patients who were pain free at two hours and the
proportion who are sustained pain free at 24 and
Table 3. Continued
Frovatriptan (94) FroDex 25 mg (95) FroDex 37.5mg (92)
n(%) n(%) n(%)
Drug related All Drug related All Drug related All
Flushing – – – – 1 (1) 1 (1)
Total adverse events 9 (10) 19 (20) 11 (12) 22 (23) 6 (7) 18 (20)
Total patients (%) 3 (3) 9 (10) 10 (11) 18 (19) 5 (5) 15 (16)
FroDex: frovatriptan þdexketoprofen; SAE: severe adverse event.
24%
(22/93)
23%
(21/93)
22%
(6/27)
*
43%
(41/95) 36%
(34/95) 29%
(14/48)
*
42%
(38/91) 33%
(30/91)
28%
(13/46)
0
10
20
30
40
50
60
70
80
90
100
SPF 24h SPF 48h Recurrence 48h
Proportion (%)
Frova FroDex 25 mg FroDex 37.5 mg
--
--
--
--
--
--
--
--
--
--
--
--
--
--
--
--
--
--
Figure 3. Proportion (%) of sustained pain free at 24 and 48 hours and relapse at 48 hours after administration of Frova, FroDex25
and FroDex37.5 in the 279 patients of the FAS population. Asterisks indicate a statistically significant difference (p<0.05) between the
group treated with frovatriptan alone and the groups treated with combination therapy.
Frova: frovatriptan 2.5 mg alone; FroDex25: frovatriptan 2.5 mg þdexketoprofen 25 mg; FroDex37.5: frovatriptan 2.5 mg þ
dexketoprofen 37.5 mg.
Tullo et al. 443
48 hours; dexketoprofen is well known to have a short
half-life and its sustained effect is not relevant.
Our study also did not include a placebo arm; in this
way it was not possible to take into account the placebo
effect, which is large and highly variable in migraine
studies (32).
Finally, the results should be interpreted cautiously
as some results may be due to chance, because statis-
tical adjustment for multiple comparisons was not fore-
seen and performed in the study protocol and statistical
analysis plan.
Conclusion
In our study comparison of both combination thera-
pies, on primary and secondary end points showed no
statistically significant differences.
Regarding the comparison of combination therapy
versus monotherapy, the results from this study are
consistent with those of a comparison between
sumatriptan alone and sumatriptan plus naproxen
sodium: the combination of the NSAID and a triptan
resulted in superior clinical benefits over monother-
apy (25). The efficacy of triptans plus NSAIDs in
general compared with triptan monotherapy might,
in part, be explained by the fact that the combination
therapy targets multiple pathogenic mechanisms in
migraine (25).
Finally, results from this study need to be confirmed
by larger clinical trials.
Clinical implications
.A randomized controlled trial (RCT) with 314 subjects with history of migraine (with or without aura) using
three different treatments for migraine attacks has never been compared before.
.The primary efficacy end point was pain free at two hours, making the results comparable with other RCTs
on migraine.
.Secondary end points (pain relief, sustained pain free, relapse within 48 hours) are also common to several
RCTs on migraine.
.Demonstration that frovatriptan plus dexketoprofen is, in broad terms, superior to frovatriptan alone.
Funding
This work was supported by Istituto Lusofarmaco d’Italia.
Conflicts of interest
All authors have occasionally served as scientific consult-
ants for manufacturers of frovatriptan. Dario Zava and
Deborha Pezzola are employees of the manufacturer of
frovatriptan.
Author contributions
Coordinator: Prof G Bussone (Milano). Investigators: GL
Mancardi (Genova), MC Tonini (Garbagnate), M Guidotti
and M Mauri (Como), R Cerbo (Roma), M Gionco (Torino),
G Comi (Milano), G Rapisarda (Catania), M Aguggia (Asti),
A Ganga (Sassari), M Bartolini (Ancona), R Sterzi (Milano),
B Panascia and R Rapisarda (Catania) and R De Simone
(Napoli).
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