REVIEW
Eslica bazepine ace a e: i s e ec i eness as adjunc i e he apy
in clinical ials and open s udies
S. D. Sho on
1
•E. T inka
2,8
•B. J. S einho
3
•M. Hol kamp
4
•V. Villanue a
5
•
J. Pel ola
6
•E. Ben-Menachem
7
Recei ed: 4 Oc obe 2016 / Accep ed: 8 No embe 2016 / Published online: 18 Janua y 2017
ÓThe Au ho (s) 2016. This a icle is published wi h open access a Sp inge link.com
Abs ac Eslica bazepine ace a e (ESL) is a once-daily
an iepilep ic d ug ha is app o ed as adjunc i e he apy in
adul s wi h ocal-onse seizu es. Following o al adminis-
a ion, ESL is apidly me abolized o i s ac i e me aboli e,
eslica bazepine, which ac s p ima ily by enhancing slow
inac i a ion o ol age-ga ed sodium channels. The e i-
cacy and sa e y/ ole abili y o ESL in he adjunc i e se ing
we e es ablished in a comp ehensi e Phase III p og am
(n=1702 andomized pa ien s) and his e idence has been
suppo ed by se e al open s udies (n=864). ESL ea -
men has demons a ed imp o emen s in heal h- ela ed
quali y o li e, in bo h andomized clinical ials and open
s udies. ESL has also been shown o be usually well ol-
e a ed and e icacious when used in he adjunc i e se ing
in elde ly pa ien s. The e ec i eness o ESL as he only
add-on o an iepilep ic d ug mono he apy has been
demons a ed in a mul ina ional s udy (n=219), subg oup
analyses o which ha e also shown i o be e icacious and
gene ally well ole a ed in pa ien s who had p e iously no
esponded o ca bamazepine he apy. Open s udies ha e
also demons a ed imp o emen s in ole abili y in pa ien s
swi ched o e nigh om oxca bazepine o ESL. Due o
di e ences in pha macokine ics, pha macodynamics, and
me abolism, he e may be clinical si ua ions in which i is
app op ia e o conside swi ching pa ien s om oxca -
bazepine o ca bamazepine o ESL.
Keywo ds Adjunc i e he apy An iepilep ic d ug 
Clinical p ac ice Epilepsy Eslica bazepine ace a e 
Focal-onse seizu es
In oduc ion
Eslica bazepine ace a e (ESL) is a once-daily (OD)
an iepilep ic d ug (AED) ha is app o ed in Eu ope as
adjunc i e he apy in adul s wi h ocal-onse seizu es, wi h
o wi hou seconda y gene aliza ion [1], and, in he USA,
o he ea men o ocal-onse seizu es as mono he apy o
adjunc i e he apy [2]. The e icacy and sa e y/ ole abili y
o ESL as adjunc i e he apy o ocal-onse seizu es in
adul s ha e been es ablished in se e al andomized, dou-
ble-blind, placebo-con olled, Phase III ials [3–6] and
long- e m ex ension s udies [7–9]. In addi ion, an open-
label, non-con olled Phase III ial has assessed he sa e y
and e icacy o adjunc i e ESL ea men in elde ly pa ien s
(aged C65 yea s) [10].
&S. D. Sho on
[email p o ec ed]
1
UCL Ins i u e o Neu ology, Box 5, Na ional Hospi al o
Neu ology and Neu osu ge y, Queen Squa e,
London WC1N 3BG, UK
2
Depa men o Neu ology and Neu oscience Ins i u e a
Ch is ian Dopple Klinik, Pa acelsus Medical Uni e si y
Salzbu g, Ignaz Ha e s asse 79, 5020 Salzbu g, Aus ia
3
Epilepsiezen um Ko k, Lands aße 1, 77694 Kehl-Ko k,
Ge many
4
Epilepsy-Cen e Be lin-B andenbu g, Depa men o
Neu ology, Cha i e
´-Uni e si a
¨ smedizin Be lin, Cha i e
´pla z
1, 10117 Be lin, Ge many
5
Mul idisciplina y Epilepsy Uni , Neu ology Se ice, Hospi al
Uni e si a io y Polo e
´cnico La Fe, A da Fe nando Ab il
Ma o ell 106, 46026 Valencia, Spain
6
Depa men o Neu ology, Tampe e Uni e si y Hospi al,
PO Box 2000, 33521 Tampe e, Finland
7
Ins i u e o Neu oscience and Physiology, Sahlg enska
Academy, Uni e si y o Go
¨ ebo g, Box 430,
SE-405 30 Go
¨ ebo g, Sweden
8
Cen e o Cogni i e Neu oscience, 5020 Salzbu g, Aus ia
123
J Neu ol (2017) 264:421–431
DOI 10.1007/s00415-016-8338-2
Con olled clinical ials a e essen ial in he licensing
p ocess o a new AED, bu hey ypically employ s ic
inclusion/exclusion c i e ia and igid dosing and i a ion
schedules; whe eas, in e e yday clinical p ac ice, pa ien s
a e mo e di e se in e ms o clinical cha ac e is ics, such as
age, como bidi ies and comedica ions, and ea men is
indi idualized o each pa ien ’s needs [11,12]. ‘Real-
wo ld’ open s udies a e, he e o e, equi ed o complemen
e idence om clinical ials, by de e mining how he
e icacy o an agen ansla es in o e ec i eness in clinical
p ac ice and by p o iding p agma ic guidance on op imal
dosing and i a ion schedules. An aspec o de e mining
he e ec i eness o a ea men is o assess i s impac on
pa ien s’ quali y o li e (QoL). This is pa icula ly impo -
an o ch onic condi ions, such as epilepsy, whe e he
e ec i eness o ea men elies i s and o emos on he
pa ien ’s willingness and abili y o be complian wi h he
ea men o e he long e m. Since i s app o al, ESL’s
sa e y and e ec i eness ha e been in es iga ed in open,
unblinded s udies [13–17], and i s e ec s on QoL ha e
been in es iga ed in bo h he clinical ial se ing and open
s udies [7,8,13,18].
The aims o his a icle we e o p o ide a b ie o e iew
o ESL’s pha macology and o e iew cu en clinical
e idence o ESL as an adjunc i e ea men o adul s wi h
ocal-onse seizu es, om he Phase III clinical ials and
some subs an ial open, unblinded s udies.
ESL pha macology
Following o al adminis a ion, ESL is apidly and ex en-
si ely me abolized by i s -pass hepa ic hyd olysis o esli-
ca bazepine (S-lica bazepine), he ac i e me aboli e
esponsible o i s pha macological e ec [19]. Eslica -
bazepine accoun s o app oxima ely 94% o plasma d ug
exposu e ollowing o al adminis a ion o ESL, o he
moie ies being R-lica bazepine (*5%) and oxca bazepine
(OXC; 1%) [20]. Eslica bazepine displays linea pha -
macokine ics a clinically ele an ESL doses and i s
e ec i e hal -li e is 20–24 h [21].
ESL is a membe o he dibenzazepine amily o
AEDs, which also includes OXC and ca bamazepine
(CBZ) [22]. ESL sha es wi h OXC and CBZ he
dibenzazepine nucleus bea ing he 5-ca boxamide sub-
s i u e, bu is s uc u ally di e en om hese agen s a
he 10,11-posi ion [21,23], esul ing in di e ences in
pha macokine ics, pha macodynamics, and me abolism
[24]. Whe eas ESL is s e eoselec i ely me abolized p i-
ma ily o eslica bazepine, OXC is me abolized o bo h
eslica bazepine and R-lica bazepine, as well as being
de ec able in se um as he pa en compound [20].
Al hough exposu e o eslica bazepine, assessed as a ea
unde he ime–concen a ion cu e (AUC), is simila ol-
lowing adminis a ion o OXC 600 mg wice daily and ESL
1200 mg OD (OXC/ESL a io o AUC: 97% o plasma
and 112% o ce eb ospinal luid [CSF]), exposu e o R-li-
ca bazepine is highe o OXC han o ESL (OXC/ESL
a io o AUC:417% o plasmaand407% o CSF),asis
exposu e o oxca bazepine (OXC/ESL a io o AUC: 411%
o plasma and 327% o CSF) [20]. ESL’s s e eoselec i e
me abolism, he e o e, a oids he ea ly peak in OXC con-
cen a ion obse ed in plasma and CSF ollowing immedi-
a e- elease OXC adminis a ion (Fig. 1), which co ela es
wi h OXC- ela ed ad e se e en s (AEs; e.g., dizziness,
headache) [20]. This di e ence may explain he inding
om clinical ials ha ESL is associa ed wi h ewe neu-
ological AEs han immedia e- elease OXC [25]. Mo eo e ,
a e ospec i e, single-cen e s udy o 21 pa ien s demon-
s a ed ha pa ien s swi ched o e nigh om immedia e- e-
lease OXC o ESL showed imp o ed ole abili y, as
assessed using he Ad e se E en s P o ile ques ionnai e
[26]. ESL also po en ially di e s om CBZ in e ms o i s
ole abili y p o ile, since CBZ me abolism is associa ed wi h
he gene a ion o oxic me aboli es, whe eas ESL me abo-
lism is no [27,28]. Fu he mo e, CBZ is a po en enzyme
induce , educing he du a ion and ac ion o many d ugs
[29], and his con ibu es o he de elopmen o como -
bidi ies such as os eopo osis, sexual dys unc ion, and as-
cula disease [29,30]. Eslica bazepine, he main ac i e
me aboli e o ESL a e o al adminis a ion in humans, is a
weak induce o cy och ome P450 3A4 and u idine 50-
diphospho-glucu onosyl ans e ases [1],bu i isaless
po en enzyme induce han CBZ. I should be no ed ha ,
since eslica bazepine dec eases exposu e o he o al con-
acep i es, le ono ges el and e hinyles adiol, mos likely
due o induc ion o cy och ome P450 3A4, women o
childbea ing po en ial should use adequa e con acep ion
du ing ESL ea men and up o he end o he cu en
mens ua ion cycle a e ea men has been discon inued [1].
I is hough ha eslica bazepine ac s p ima ily by
educing he a ailabili y o ol age-ga ed sodium channels
(VGSCs) h ough enhancemen o slow inac i a ion [31],
and, he e o e, di e s om CBZ, which ac s by al e ing he
as inac i a ion o VGSCs [31]. Eslica bazepine’s appa -
en a ini y o VGSCs in he inac i a ed s a e is app oxi-
ma ely wo- old less han ha o CBZ [32] and i s appa en
a ini y o VGSCs in he es ing s a e is 5- o 15- old lowe
han hose o CBZ, OXC, and (R)-lica bazepine [19].
Eslica bazepine, he e o e, appea s o ha e enhanced
inhibi o y selec i i y o apidly i ing ‘epilep ic’ neu ons
o e hose wi h no mal ac i i y [19,33,34]. The clinical
signi icance o hese di e ences is cu en ly no known, bu
hey could po en ially play a ole in he obse ed e icacy
o ESL in he p esence o CBZ esis ance [35,36].
Expe imen s using pa ch-clamp eco ding in human and a
422 J Neu ol (2017) 264:421–431
123
hippocampal slices ha e demons a ed ha eslica bazepine
exhibi s main ained use-dependen blocking e ec s, wi h
signi ican add-on e ec s o CBZ in human epilepsy [36].
These indings a e suppo ed by ESL clinical ial da a
demons a ing ha ESL may be e ec i e in pa ien s whose
seizu es a e uncon olled by CBZ [3–6,37]. Eslica -
bazepine also di e s om CBZ and R-lica bazepine in i s
e ec s on Ca
V
3.2 inwa d cu en s, sub-maximal GABA
cu en s, K
V
7.2 ou wa d cu en s, and glycine GlyRa3
ecep o -media ed inwa d cu en s [34]. Al hough he
po en ial clinical signi icance o hese di e ences is also
no ye known, ESL has been shown o exhibi s ong
an iepilep ogenic e ec s in expe imen al models o epi-
lepsy ha may in pa be due o i s inhibi o y e ec s on
Ca
V
3.2 T- ype Ca
2?
channels [36].
ESL Phase III clinical ial da a
Da a om andomized, double-blind,
placebo-con olled, Phase III ials
The e icacy and sa e y/ ole abili y o ESL as adjunc i e
he apy in adul s wi h ocal-onse seizu es ha e been
in es iga ed in ou in e na ional, mul icen e , Phase III
ials: S udies 301 [3], 302 [4], 303 [5], and 304 [6]. All o
hese indi idual Phase III ials me hei p ima y end-
poin s. The esul s o a pos hoc analysis o pooled da a
om he andomized, double-blind, placebo-con olled
pe iods o S udies 301, 302, and 303 will be p esen ed he e
[38]. Subsequen indings om S udy 304 [6] and a pos
hoc pooled analysis o S udies 301, 302, and 304 [39–41]
a e consis en wi h he indings o he pooled analysis o
S udies 301, 302, and 303 ou lined below. ESL was
licensed as an adjunc i e ea men o ocal-onse seizu es
by he Eu opean Medicines Agency on he basis o S udies
301, 302, and 303 [1], and by he Uni ed S a es Food and
D ug Adminis a ion on he basis o S udies 301, 302, and
304 [2].
Summa y o pooled analysis o s udies 301, 302, and 303
The ials included pa ien s aged C18 yea s wi h a docu-
men ed diagnosis o epilepsy and a leas a 12-mon h his o y
o simple o complex ocal-onse seizu es, wi h o wi hou
seconda y gene aliza ion [38]. Pa ien s we e also equi ed o
be ea ed wi h s able doses o one o wo AEDs (one o h ee
AEDs in S udy 302). The p ede ined key e icacy endpoin s
o he pooled analysis we e seizu e equency du ing he
12-week main enance pe iod (adjus ed pe 4 weeks), ela-
i e educ ion om baseline in seizu e equency, and
esponde a e ( esponse de ined as C50% seizu e equency
educ ion om baseline). These endpoin s we e assessed o
he in en ion- o- ea (ITT) and pe p o ocol (PP) popula-
ions. Sa e y assessmen s included ea men -eme gen AEs
(TEAEs), clinical labo a o y pa ame e s, i al signs, and
elec oca diog aphy (ECG) [38].
Da a ob ained om 1049 pa ien s en olled a 125 cen e s
in 23 coun ies we e pooled and analyzed [38]. The majo i y
o he popula ion was Caucasian and app oxima ely 50% o
pa ien s we e males. The mean age was app oxima ely
37 yea s and he mean du a ion o epilepsy was 22 yea s.
Compa ed wi h placebo, he e was a s a is ically signi ican
educ ion in seizu e equency du ing he main enance
ab
Fig. 1 Plasma (a) and CSF (b) concen a ion– ime p o iles o OXC
ollowing he las dose o a epea ed-dose egimen o once-daily ESL
1200 mg and wice-daily OXC 600 mg o heal hy olun ee s (n=7
in each g oup o plasma p o ile; n=6 in each g oup o CSF
p o ile). CSF ce eb ospinal luid, ESL eslica bazepine ace a e, OXC
oxca bazepine. Adap ed om Nunes e al. [20] wi h pe mission om
John Wiley and Sons
J Neu ol (2017) 264:421–431 423
123
pe iod wi h ESL 800 mg/day and ESL 1200 mg/day in bo h
he ITT and PP popula ions (p 0.0001; Fig. 2a). The
median ela i e educ ion in seizu e equency was 35% wi h
ESL 800 mg/day and 39% wi h ESL 1200 mg/day, com-
pa ed wi h 15% wi h placebo (ITT popula ion). Simila ly,
he esponde a e was signi ican ly highe o ESL
800 mg/day (36%) and ESL 1200 mg/day (44%), compa ed
wi h placebo (22%) (p=0.0001 and p 0.0001, espec-
i ely; ITT popula ion; Fig. 2b) [38].
The incidence o TEAEs was highe o ESL han o
placebo and inc eased wi h ESL dose (Table 1)[38]. The
majo i y o TEAEs we e o mild o mode a e in ensi y. The
mos equen ly epo ed TEAEs (C10% o pa ien s in any
ea men g oup) we e dizziness, somnolence, headache,
and nausea (Table 1). Di e ences in he equencies o
TEAEs be ween he ESL and placebo g oups we e mainly
obse ed du ing he i s 6 weeks o ea men , a e which
he equencies ac oss g oups we e simila . TEAEs leading
o discon inua ion we e also dose- ela ed (Table 1); hese
we e mainly e igo, diplopia, blu ed ision, nausea and
omi ing, a igue, abno mal coo dina ion, dizziness, head-
ache, and somnolence. No dose-dependen end was
obse ed o se ious TEAEs. Only one pa ien died du ing
he s udy (placebo g oup). Changes in mean clinical lab-
o a o y pa ame e s did no yield clinically ele an indings
and he e we e no changes in i al signs o body weigh o
clinical conce n. Hypona emia 125 mM was epo ed in
ou pa ien s [ESL 400 mg/day, n=1 (0.5%); ESL
800 mg/day, n=2 (0.7%); ESL 1200 mg/day, n=1
(0.4%)]. All ou pa ien s we e concomi an ly ea ed wi h
CBZ a C1000 mg/day and all had sodium le els
135 mM a baseline. ESL ea men was associa ed wi h
no clinically ele an ECG indings. No clinically signi i-
can p olonga ion o he QTc in e al was obse ed in any
pa ien [38].
In luence o s a ing dose and dose i a ion
scheme on incidence o TEAEs
The in luence o s a ing dose and dose i a ion scheme on
he incidence o TEAEs du ing ea men wi h ESL was
examined as pa o he pos hoc pooled analysis o S udies
301, 302, and 304 [41]. Du ing he 2-week i a ion pe iod,
he e was a ma ked di e ence be ween he TEAE p o ile o
he ESL 800 mg/day ‘wi hou - i a ion’ g oup and he ESL
800 mg/day ‘wi h- i a ion’ g oup, he incidence o all o
he mos equen ly epo ed TEAEs being highe wi hou
i a ion han wi h. The g ea es di e ences we e o
dizziness (24.9 s. 8.5%), somnolence (15.9 s. 5.5%),
headache (10.8 s. 4.5%), nausea (12.2 s. 3.0%), omi ing
(7.3 s. 1.0%), and a axia (6.1 s. 0.5%). Among he
ea men g oups wi h a a ge dose o ESL 800 o
1200 mg/day, he equency o he mos commonly
epo ed TEAEs was highe o hose ini ia ed a
800 mg/day e sus 400 mg/day. The equency o TEAEs
in he ESL 800 mg/day ‘wi h- i a ion’ and ESL
1200 mg/day ‘wi h- i a ion’ g oups was simila o he ESL
400 mg/day g oup, and no ma kedly di e en om pla-
cebo. The incidence o ash did no appea o be ela ed o
ESL s a ing dose o o he a e o dose escala ion, bu was
highe among pa ien s main ained on ESL 1200 mg/day
(2.6–4.9%) han among pa ien s main ained on ESL
a
b
Fig. 2 E icacy analysis o pooled da a om Phase III S udies 301,
302, and 303: a ela i e educ ion om baseline in seizu e equency
du ing 12-week main enance ea men wi h adjunc i e ESL (ITT
popula ion) and b esponde a e du ing 12-week main enance
ea men wi h adjunc i e ESL (ITT popula ion) [38] ep in ed wi h
pe mission om John Wiley and Sons. Response was de ined as
C50% educ ion om baseline in seizu e equency; p- alues e e o
compa ison s. placebo. CI con idence in e al, ESL eslica bazepine
ace a e, ITT in en ion- o- ea , LS leas squa es
424 J Neu ol (2017) 264:421–431
123
800 mg/day (0.0–1.9%), ESL 400 mg/day (0.5%), o pla-
cebo (0.9%) [41].
O e all, hese Phase III andomized, con olled ial da a
demons a ed ha ESL was e ec i e and well ole a ed as
an adjunc i e he apy o adul s wi h ocal-onse seizu es
[3–6,38–41]. ESL led o dose- ela ed imp o emen s in
mos e icacy ou comes, he e ec i e dose ange being
800–1200 mg OD [38]. The o e all incidence o TEAEs
was highe a highe doses o ESL, which appea s
a ibu able o expec ed AEs, such as diplopia, dizziness,
headache, e igo, and somnolence. The incidence o se i-
ous TEAEs in hese s udies was low. TEAEs we e gene ally
p edic able, manageable, occu ed du ing he ea ly s ages o
ea men , and we e o mild o mode a e in ensi y [38]. The
pooled analysis o S udies 301, 302, and 304 also indica ed
ha he equency o TEAEs wi h ESL may be minimized
by use o an app op ia e i a ion scheme [41].
Da a om open-label Phase III s udies
ESL sa e y/ ole abili y and e icacy in elde ly pa ien s
The sa e y/ ole abili y and e icacy o adjunc i e ESL
he apy in elde ly pa ien s (aged C65 yea s) wi h ocal-
onse seizu es we e assessed in a mul icen e , open-label,
non-con olled, single-a m Phase III ial [10]. The ial
employed lexible doses o ESL (400–1200 mg OD), in
acco dance wi h he ecommenda ions app o ed by he
egula o y au ho i y [1]. Pa ien s we e included i hey had
a leas wo ocal-onse seizu es du ing he 8-week baseline
pe iod and we e being ea ed wi h one o wo AEDs o he
han OXC. A e an 8-week baseline pe iod, pa ien s
en e ed a 26-week main enance pe iod, du ing which ESL
was ini ia ed a 400 mg OD and adjus ed based on indi-
idual esponse (400–1200 mg/day). Sa e y/ ole abili y
was assessed by e alua ion o TEAEs, clinical labo a o y
e alua ions, i al signs, 12-lead ECG, physical/neu ologi-
cal examina ions, No is’ scales o e alua ion o seda i e
e ec s, and he Columbia Suicide Se e i y Ra ing Scale.
E icacy was assessed as he absolu e and ela i e change
om baseline in seizu e equency (s anda dized o e-
quency pe 4 weeks), esponde a e ( esponse de ined as
C50% seizu e equency educ ion), and seizu e eedom
a e [10].
The s udy popula ion comp ised 72 pa ien s (52.8%
males), wi h a mean age o 71.6 yea s ( ange
65–84 yea s) [10]. The mean ea men du a ion was
151.8 days and he mean ESL dose du ing he o e all
ea men pe iod was 591.9 mg/day. The majo i y o
pa ien s ecei ed doses no highe han 800 mg/day. The
mos equen ly epo ed TEAEs (C5% pa ien s) we e
dizziness (12.5%), somnolence (9.7%), a igue (8.3%),
con ulsion (8.3%), hypona emia (8.3%), nasopha yngi is
(6.9%), and uppe espi a o y ac in ec ion (5.6%). The
majo i y o TEAEs we e o mild o mode a e in ensi y. In
o al, 16 se ious TEAEs we e epo ed o en (13.9%)
pa ien s; none occu ed in mo e han one pa ien . Th ee
pa ien s died bu none o he dea hs was conside ed
Table 1 Summa y o TEAEs in pooled analysis o S udies 301, 302, and 303 [38]
Placebo
(n=289)
ESL 400 mg/day
(n=196)
ESL 800 mg/day
(n=284)
ESL 1200 mg/day
(n=280)
To al ESL
(n=760)
Any TEAE, n(%) 134 (46.4) 119 (60.7) 178 (62.7) 189 (67.5) 486 (63.9)
TEAEs wi h incidence C10% in any
ea men g oup, n(%)
Dizziness 21 (7.3) 26 (13.3) 60 (21.1) 81 (28.9) 167 (22.0)
Somnolence 27 (9.3) 21 (10.7) 37 (13.0) 42 (15.0) 100 (13.2)
Headache 25 (8.7) 17 (8.7) 29 (10.2) 38 (13.6) 84 (11.1)
Nausea 6 (2.1) 10 (5.1) 21 (7.4) 28 (10.0) 59 (7.8)
TEAEs conside ed possibly ela ed o ESL
ea men , n(%)
72 (24.9) 75 (38.3) 134 (47.2) 154 (55.0) 363 (47.8)
TEAEs by se e i y, n(%)
Mild 56 (19.4) 56 (28.6) 72 (25.4) 56 (20.0) 184 (24.2)
Mode a e 65 (22.5) 45 (23.0) 82 (28.9) 101 (36.1) 228 (30.0)
Se e e 13 (4.5) 18 (9.2) 24 (8.5) 32 (11.4) 74 (9.7)
TEAEs leading o discon inua ion, n(%) 13 (4.5) 17 (8.7) 33 (11.6) 54 (19.3) 104 (13.7)
Any se ious TEAE, n(%) 4 (1.4) 9 (4.6) 10 (3.5) 9 (3.2) 28 (3.7)
Dea hs, n(%) 1 (0.3) 0 0 0 0
ESL eslica bazepine ace a e, TEAE ea men -eme gen ad e se e en
J Neu ol (2017) 264:421–431 425
123

ela ed o s udy medica ion. Six een (22.2%) pa ien s
discon inued due o TEAEs. TEAEs leading o discon-
inua ion o mo e han one pa ien we e hypona emia
(n=3), dizziness (n=2), and a igue (n=2). Labo a-
o y- ela ed TEAEs a ec ing mo e han one pa ien we e
hypona emia (8.3%), inc eased blood c ea ine phospho-
kinase (4.2%), and inc eased gamma-glu amyl ans e ase
(4.2%). Fo i al signs, ECG, and physical and neu o-
logical examina ions, no ends we e obse ed and he
incidence o ele an indings was low. The No is’
adap ed men al seda ion scales showed mino changes in
pa ien esponses owa ds a sligh wo sening o mean
alues. The e we e no epo s o suicidali y pos baseline,
as assessed by he Columbia Suicide Se e i y Ra ing
Scale and TEAE epo ing [10].
Fo he ull analysis se (n=71), he esponde and sei-
zu e eedom a es du ing he main enance pe iod we e 54.9
and 15.5%, espec i ely [10]. The co esponding alues o
he PP se (n=55) we e 56.4 and 12.7%, espec i ely. The
mean (s anda d de ia ion) s anda dized seizu e equency
dec eased om 4.8 (5.5) du ing he 8-week baseline pe iod o
3.6 (5.8) du ing he 26-week main enance pe iod ( ull anal-
ysis se ). O e all, he s udy ound ha adjunc i e ea men
wi h ESL (400–1200 mg OD) in elde ly pa ien s wi h ocal-
onse seizu es was e icacious and did no aise any unex-
pec ed sa e y conce ns [10].
Impac o ESL on QoL
Du ing he 1-yea , open-label ex ension s udies o he
Phase III adjunc i e he apy ials, pa ien s we e ea ed
wi h lexible ESL dosing (400–1200 mg/day) acco ding o
esponse and ole abili y [7–9]. These s udies included an
assessmen o he long- e m impac o adjunc i e ESL
ea men on heal h- ela ed QoL, by employing he Quali y
o Li e in Epilepsy In en o y-31 (QOLIE-31) ques ionnai e
[42] a baseline o he ini ial Phase III ial and a he end o
1-yea open-label ea men o a ea ly discon inua ion
[7,8,18]. In he open-label ex ension o S udy 301,
QOLIE-31 sco es inc eased (i.e., imp o ed) om baseline
o he las assessmen and he imp o emen was s a is i-
cally signi ican o all subscales excep emo ional well-
being [7]. The mean ela i e imp o emen in QOLIE-31
subscale sco es anged om 7.1 (emo ional well-being) o
51.4 (seizu e wo y), and he o e all mean sco e imp o ed
om 54.8 a baseline o 58.3 a he las assessmen
(p 0.0001) [7]. Simila imp o emen s in QOLIE-31
sco es we e obse ed in he open-label ex ensions o S udy
302 (signi ican imp o emen s in he o e all QoL, seizu e
wo y, and medica ion e ec s subscales and o e all sco e)
[8] and S udy 303 (signi ican imp o emen s in all sub-
scales and o e all sco e) [18].
Phase IV open s udy da a
EPOS s udy
The Eslica bazepine ace a e in Pa ial-Onse Seizu es
(EPOS) s udy was a p ospec i e, non-in e en ional, open-
label in es iga ion conduc ed in 88 si es ac oss eigh
Eu opean coun ies [13]. I s objec i es we e o assess he
e en ion a e, seizu e con ol, sa e y/ ole abili y and e ec
on QoL o ESL as add-on o an iepilep ic mono he apy in
e e yday clinical p ac ice. Adul pa ien s wi h ocal-onse
seizu es (wi h o wi hou seconda y gene aliza ion),
insu icien ly con olled unde AED mono he apy, we e
o e ed pa icipa ion in he s udy i hei clinician had
p e iously and independen ly decided o ini ia e ESL add-
on he apy. ESL was ecommended o be used acco ding o
app o ed guidance [1]. The p ima y endpoin was e en ion
a e a e 6 mon hs. O he assessmen s included e en ion
a e a e 3 mon hs, and e icacy, sa e y/ ole abili y, and
QoL a e 3 and 6 mon hs. E icacy was assessed as seizu e
equency du ing he p e ious 3 mon hs, esponde a e
( esponse de ined as C50% seizu e equency educ ion
om baseline), and seizu e eedom a e (seizu e eedom
de ined as no seizu es wi hin he p e ious 3 mon hs).
Sa e y/ ole abili y was assessed by e alua ing AEs and
ad e se d ug eac ions, de ined as AEs wi h causal ela-
ionship o s udy d ug. QoL was assessed using he pa ien -
a ed Quali y o Li e in Epilepsy In en o y-10 (QOLIE-10)
[13,43].
A o al o 219 pa ien s we e included in he s udy [13].
The median age was 43 yea s ( ange 18–83 yea s) and
57.5% we e males. The mean ime since epilepsy diagnosis
was 12.3 yea s ( ange 0–57.3 yea s). Mos pa ien s
(74.3%) ecei ed a a ge ESL dose o 800 mg/day. Fo he
majo i y o pa ien s (79.3%), he a ge dose was eached
wi h one i a ion s ep. The mos commonly used baseline
AED mono he apies (C5% o pa ien s) we e le e i ace am
(37.9%), lamo igine (24.7%), alp oa e (13.7%), and
ca bamazepine (6.4%). The 6-mon h e en ion a e was
82.2% [95% con idence in e al (CI) 76.5–87.0%] and he
3-mon h e en ion a e was 89.0% (95% CI: 84.1–92.9%).
A e 3 and 6 mon hs, esponde a es we e 69.9 and
81.8%, espec i ely, and seizu e eedom a es we e 25.9
and 39.2%, espec i ely (Fig. 3). AEs we e epo ed o
26.0% o pa ien s and ad e se d ug eac ions o 22.4% o
pa ien s. Eigh pa ien s (3.7%) expe ienced se ious AEs.
No AE was epo ed o [5% o pa ien s. The mos e-
quen ly epo ed AEs we e dizziness (4.6%), headache
(3.2%), con ulsion (3.2%), and a igue (2.7%). The mean
QOLIE-10 sco e dec eased (i.e., imp o ed) om 2.9
(n=128) a baseline o 2.4 (n=114) a e 3 mon hs and
2.1 (n=109) a e 6 mon hs [13].
426 J Neu ol (2017) 264:421–431
123
Pos hoc subg oup analyses we e conduc ed o hose
45 pa ien s in EPOS who had documen ed non- esponse o
his o ic CBZ ea men [44] and he 41 pa ien s aged
[60 yea s [45]. E icacy, sa e y/ ole abili y, and he impac
o ea men on QoL we e assessed as o he o e all
popula ion [13]. In he subg oup o pa ien s who had p e-
iously no esponded o CBZ ea men , he e en ion,
esponde , and seizu e eedom a es a e 6 mon hs we e
88.9% (95% CI: 75.9–96.3%), 95.1% (95% CI:
83.5–99.4%), and 33.3% (95% CI: 19.6–49.5%), espec-
i ely, and he mean QOLIE-10 sco e dec eased om 2.8
(n=21) a baseline o 2.2 (-13.0%; n=18) a e
6 mon hs [44]. Two AEs we e epo ed o wo (4.4%)
pa ien s and bo h we e hypona emia [44]. Simila ly, o
he elde ly pa ien s included in EPOS, he e en ion,
esponde , and seizu e eedom a es a e 6 mon hs we e
78.0% (95% CI: 62.4–89.4%), 83.3% (95% CI:
65.3–94.4%), and 56.3% (95% CI: 37.7–73.6%), espec-
i ely, and he mean QOLIE-10 sco e dec eased om 2.7
(n=28) a baseline o 2.2 (-14.5%; n=24) a e
6 mon hs [45]. Twel e AEs we e epo ed o six (14.6%)
pa ien s and no AE was epo ed in [5% o pa ien s. The
mos equen ly epo ed AEs we e dizziness (4.9%) and
alle gic de ma i is (4.9%) [45].
O e all, he EPOS s udy demons a ed ha ESL as add-
on o an iepilep ic mono he apy was associa ed wi h
a o able e en ion and seizu e con ol, and was well ol-
e a ed by he majo i y o adul pa ien s [13]. ESL ea men
also esul ed in imp o emen s in pa ien - a ed QoL [13]in
pa ien s who we e less se e ely ill a baseline han hose
en olled in clinical ials. Mo eo e , ESL was shown o be
e ec i e and gene ally well ole a ed when used in elde ly
pa ien s, and in hose who had p e iously no esponded o
CBZ he apy [44,45].
Spanish ESLIBASE s udy
The ESLIBASE s udy was a mul icen e , e ospec i e,
non-in e en ional s udy unde aken o e alua e he long-
e m e icacy and sa e y o adjunc i e ESL he apy in
pa ien s wi h ocal epilepsy in a clinical p ac ice se ing
[14]. Conduc ed in 12 hospi als in Spain, he s udy inclu-
ded pa ien s wi h a diagnosis o epilepsy and ocal-onse
seizu es who we e ea ed wi h ESL acco ding o clinical
p ac ice and whose ESL ea men was ini ia ed be ween
Janua y 2010 and July 2012. Da a we e collec ed e o-
spec i ely a baseline and a 3, 6, and 12 mon hs. E icacy
assessmen s included esponde a e ( esponse de ined as
C50% seizu e equency educ ion om baseline), seizu e
eedom a e, and e en ion a e, all assessed a e 3, 6, and
12 mon hs. Sa e y assessmen s included e alua ion o AEs
[14].
The s udy popula ion comp ised 327 pa ien s (52.0%
emale) wi h a mean age o 41.9 yea s ( ange 14–87 yea s)
[14]. Fo mos pa ien s, ESL was ini ia ed a 400 mg/day as
a single dose and up- i a ed in 400-mg inc emen s e e y 7,
10, o 14 days un il he op imal dose was eached. The
maximal app o ed dose (1200 mg/day) was exceeded i
deemed necessa y; 26 (7.9%) pa ien s we e aking doses
[1200 mg/day a las obse a ion. The median ESL dose
a Mon hs 3, 6, and 12 was 800, 1200, and 1200 mg/day,
espec i ely (Villanue a, pe sonal communica ion), wi h
doses anging om 400 o 2000 mg/day a e e y imepoin .
The e was a signi ican dec ease in mean numbe o con-
comi an AEDs used om baseline (2.0) o las ollow-up
(1.6; p 0.001) [14].
Re en ion a es a e 3, 6, and 12 mon hs we e 89.3,
80.1, and 72.5%, espec i ely [14]. A e 12 mon hs,
52.5% o pa ien s we e esponde s and 25.3% o pa ien s
we e seizu e ee (Fig. 4). The cumula i e a e o AEs ha
we e possibly ela ed o ESL ea men was 40.7% a
12 mon hs. The mos commonly epo ed TEAEs (C5% o
pa ien s) we e dizziness/nausea (11.3%), somnolence
(6.1%), and a axia (5.1%). Rash/p u i us was epo ed o
12 (3.6%) pa ien s and hypona emia ( anging om
116–128 mEq/L) was epo ed o nine (2.7%) pa ien s.
The majo i y o AEs we e mild o mode a e in in ensi y.
The cumula i e a e o AEs leading o ea men discon-
inua ion was 16.2% a e 12 mon hs. O 26 pa ien s who
we e ansi ioned om OXC o ESL due o OXC- ela ed
AEs, 15 (57.7%) no longe had AEs a e ansi ioning o
ESL. Simila ly, o 17 pa ien s who we e ansi ioned om
CBZ o ESL due o CBZ- ela ed AEs, eigh (47.1%) no
longe had AEs a e ansi ioning o ESL [14].
Fig. 3 Responde and seizu e eedom a es a e 3 and 6 mon hs in
he EPOS s udy. Response was de ined as C50% seizu e equency
educ ion in he p e ious 3 mon hs, compa ed wi h he 3 mon hs p io
o ini ia ing ESL he apy. Seizu e eedom is p esen ed o o al
seizu es and by seizu e ype. n=212 a 3 mon hs; n=189 a
6 mon hs [13] ep in ed wi h pe mission om John Wiley and Sons
J Neu ol (2017) 264:421–431 427
123
O he open s udies
A e ospec i e, consecu i e, 2-yea obse a ional s udy
assessed he e icacy and ole abili y o adjunc i e ESL
he apy in 152 pa ien s (mean age 38.5 yea s; eigh pa ien s
18 yea s) ea ed a a single cen e in Po ugal [15].
Pa ien s’ mean epilepsy du a ion was 26.8 yea s and hei
mean seizu e equency in he 3 mon hs p io o ESL ini i-
a ion was 19.7 seizu es/mon h. Kaplan–Meie e en ion a es
we e 82.9, 71.3, 65.1, and 62.8% a 6, 12, 18, and 24 mon hs,
espec i ely. Re en ion was shown o be una ec ed by
gende , diagnosis, age, o epilepsy du a ion. O e all, 56
pa ien s (36.8%) discon inued ESL ea men : 32 (57.1%)
due o AEs, 19 (33.9%) due o lack o e icacy, and i e
(8.9%) due o o he easons. Responde a es a 6, 12, 18, and
24 mon hs we e 25.7, 25.7, 19.0, and 17.1%, espec i ely.
AEs we e epo ed by 64 pa ien s (42.1%), hal o whom
discon inued ESL he apy due o AEs. The mos equen ly
epo ed AEs we e dizziness and somnolence/slowness. AEs
we e mo e equen ly epo ed in ea men egimens ha
included CBZ. O e all, no new sa e y signals eme ged
compa ed wi h e idence om ESL clinical ials [15].
An obse a ional, desc ip i e, c oss-sec ional s udy was
conduc ed o assess e icacy and ole abili y in he i s 61
pa ien s o ecei e adjunc i e ESL he apy o d ug- esis-
an epilepsy a a single epilepsy uni in Spain [16]. The
mean ollow-up du a ion was 4.7 ±3.2 mon hs and he
e en ion a e a 3 mon hs was 75.4%. In 40 pa ien s wi h a
minimum ollow-up pe iod o 3 mon hs, mon hly median
seizu e equency dec eased om baseline by 63.6%
(p 0.001); 12 pa ien s (30.0%) achie ed a educ ion o
C80%, and i e (12.5%) achie ed seizu e eedom. AEs
we e epo ed by 35 pa ien s (57.4%) and mos ly occu ed
du ing i a ion. The mos commonly epo ed AE was
dizziness (34.4%). Two pa ien s expe ienced exan hema ic
cu aneous eac ions and ou pa ien s (6.6%) de eloped
hypona emia (sodium ange 128–132 mmol/L). The e
we e no sodium alues 125 mmol/L and no pa ien s
discon inued ESL due o low sodium le els. Twel e
pa ien s (19.7%) swi ched o e nigh o ESL om OXC,
using a dose a io o 1:1, and 13 pa ien s (21.3%) swi ched
o e nigh om CBZ o ESL, using a dose a io o 1:1.3.
Swi ching om OXC o ESL was ound o be e ec i e and
well ole a ed, whe eas swi ching om CBZ o ESL was
less e ec i e and less well ole a ed [16].
In ano he audi o 105 pa ien s ea ed wi h ESL a a
single uni in Spain, 20.7% o pa ien s emained seizu e- ee
and 58.4% demons a ed[50% seizu e equency educ ion
a e he in oduc ion o ESL [17]. A e 6 mon hs, 18.1% o
pa ien s had expe ienced AEs ( he mos common being
cogni i e diso de s) and 11.5% had discon inued ea men .
The addi ion o ESL o lacosamide was shown o be signi -
ican ly less e ec i e in con olling seizu es han i s addi ion
o o he AEDs, whe eas he addi ion o ESL o o he sodium
channel blocke s was shown o be simila in e icacy o i s
addi ion o o he AEDs [17].
Discussion
The clinical e icacy and sa e y/ ole abili y o adjunc i e
ESL he apy in adul s wi h ocal-onse seizu es ha e been
es ablished in a p og am o andomized, double-blind,
placebo-con olled, Phase III ials [3–6]. These ials ha e
also es ablished he e ec i eness o adjunc i e ESL he -
apy by including pa ien - epo ed ou come measu es ha
ha e demons a ed imp o emen s in heal h- ela ed QoL
o e he long e m [7,8,18]. ESL has addi ionally been
shown o be well ole a ed and e icacious when used in he
adjunc i e se ing in elde ly pa ien s wi h ocal-onse sei-
zu es [10].
ESL is app o ed in Eu ope a doses up o 1200 mg/day
as adjunc i e he apy in adul s wi h ocal-onse seizu es
[1]. Since ESL is addi ionally app o ed in he USA a
doses up o 1600 mg/day as mono he apy in adul s wi h
uncon olled ocal-onse seizu es [2], on he basis o he
indings o wo Phase III con e sion o mono he apy ials
[46,47], i emains o be de e mined whe he he
1600-mg/day dose migh also be e ec i e and well ole -
a ed in he adjunc i e se ing.
The e has been inc easing acknowledgemen o he
impo ance o open s udies in helping o in o m heal h
policy decisions, and bodies such as he In e na ional
Socie y o Pha macoeconomics and Ou comes Resea ch
ha e highligh ed he need o igo and anspa ency when
conduc ing such s udies [48,49]. In he case o ESL,
Fig. 4 Responde and seizu e eedom a es a e 3, 6, and 12 mon hs
o ESL ea men in he ESLIBASE s udy (n=327). Response was
de ined as C50% seizu e equency educ ion om baseline. Seizu e
eedom was de ined as no seizu es om he beginning o he s udy
(up o imepoin s ea lie han he 12-mon h isi ), no seizu es o he
las 6 mon hs (a he 12-mon h isi ), o no seizu es o 12 mon hs i
pa ien s we e seizu e ee in he 3 mon hs p io o s udy en y [14]
ep in ed wi h pe mission om Else ie
428 J Neu ol (2017) 264:421–431
123
clinical ial da a ha e been suppo ed by se e al open
s udies, which ha e demons a ed ha adjunc i e ESL
ea men was e ec i e and gene ally well ole a ed as
long- e m he apy in clinical p ac ice [14,15], and when
used as he only add-on o AED mono he apy in clinical
p ac ice [13]. The e ec i eness o adjunc i e ESL ea -
men in clinical p ac ice was associa ed wi h a o able
e en ion and imp o emen s in heal h- ela ed QoL [13,14].
Mo eo e , when used as he only add-on o AED
mono he apy, ESL was shown o be e icacious and gen-
e ally well ole a ed in elde ly pa ien s [45] and in pa ien s
who had p e iously no esponded o CBZ he apy [44].
Hypona emia and ash ha e been epo ed as common
AEs in pa ien s ea ed wi h ESL in clinical ials (1.2 and
1.1%, espec i ely) [1]. Highe a es o hypona emia ha e
been epo ed in elde ly pa ien s [10] and in some pos -
ma ke ing open s udies [14,16]. I is, he e o e, good
p ac ice o moni o o he po en ial de elopmen o
hypona emia wi h ESL ea men h ough labo a o y es -
ing, pa icula ly in he elde ly. Rash has also been epo ed
in some open s udies [14,16]. Neu opsychia ic and cog-
ni i e side e ec s a e epo ed uncommonly wi h ESL
ea men (C1/1000 o 1/100 pa ien s), wi h he excep ion
o dis u bance in a en ion (C1/100 o 1/10 pa ien s) [1].
The e ec i eness o ESL in pa ien s who a e esis an o
CBZ he apy may be due o di e ences be ween he agen s in
e ms o hei modes o ac ion [31,36]. Mo eo e , gi en he
pha macological di e ences be ween ESL and OXC and
CBZ [21,23,24], he e may be o he clinical si ua ions in
which i is app op ia e o conside ansi ioning pa ien s om
CBZ o OXC o ESL [50]. When ansi ioning pa ien s om
OXC o ESL, a dose a io o 1:1 is ecommended and i has
been claimed ha he change is possible o unde ake in a
single s ep, wi h no adjus men o comedica ion equi ed
[50]. The ansi ioning o pa ien s om CBZ o ESL is less
s aigh o wa d and should be ca e ully conside ed on a
case-by-case basis, aking accoun o he pa ien ’s clinical
cha ac e is ics and comedica ions, which may equi e dose
adjus men due o CBZ being a s ong induce o CYP
enzymes [50]. In gene al, a CBZ:ESL dose a io o 1:1.3
should be used and pa ien s should be ansi ioned o e a
minimum pe iod o 1–2 weeks [50] al hough longe pe iods
o swi ching a e o en ad ised. In addi ion o pa ien s who a e
esis an o CBZ he apy, clinical si ua ions in which i migh
be app op ia e o conside a ansi ion o ESL include
pa ien s who expe ience OXC- o CBZ- ela ed AEs (e.g.,
cogni i e AEs) and hose who expe ience, o a e a isk o
de eloping, me abolic p oblems esul ing om CBZ
induc ion o enzymes in ol ed in endogenous me abolic
pa hways (e.g., hype choles e olemia, os eopo osis, sexual
dys unc ion) [50]. I should be no ed, howe e , ha long-
e m ollow-up s udies a e equi ed o con i m whe he ESL
can educe he isk o he ypes o long- e m me abolic
sequelae epo ed o CBZ o no . O he pa ien s o whom i
migh be app op ia e o conside ansi ioning om CBZ o
OXC o ESL a e hose who a e poo ly complian wi h wo- o
h ee- imes daily dosing [50].
Acknowledgemen s Edi o ial suppo was p o ided by John Scopes
o mXm Medical Communica ions and unded by Eisai L d. The wo k
o SDS is suppo ed by he es a e o Ms. Susan W igh .
Compliance wi h e hical s anda ds
E hical s anda ds All human and animal s udies ou lined in his
a icle we e app o ed by he app op ia e e hics commi ee(s) and
ha e, he e o e, been pe o med in acco dance wi h he e hical s an-
da ds laid down in he 1964 Decla a ion o Helsinki and i s la e
amendmen s.
Con lic s o in e es SD. Sho on has ecei ed a el eimbu semen ,
lec u ing, and/o ad iso y boa d ees om Eisai, Bial, UCB,
GlaxoSmi hKline, Vi oPha ma, Sage, and he B i ish Medical Jou nal.
E. T inka has ac ed as a paid consul an o Eisai, E e Neu o Pha ma,
Biogen Idec, Med onic, Bial, Shi e, and UCB, and has ecei ed
speake ’s hono a ia om Bial, Eisai, Ge o Lannach, GlaxoSmi hK-
line, Boeh inge , Vi oPha ma, Ac a is, Te a, NewB idge, and UCB.
He has ecei ed esea ch unding om UCB, Biogen Idec, Red Bull,
Baye , Me ck, he Eu opean Union, and FWF O
¨s e eichische Fond zu
Wissenscha s o
¨ de ung and Bundesminis e ium u
¨ Wissenscha und
Fo schung. E. T inka and S. Sho on a e membe s on he Es ablished
S a us Epilep icus T ea men T ial (ESETT) s ee ing commi ee and co-
o ganize s o he biannual London-Innsb uck Colloquium on S a us
Epilep icus. B.J. S einho has ecei ed speake ’s hono a ia om
Desi in, Eisai, No a is, OmniaMed, and UCB. He has ac ed as a paid
consul an o Ac elion, B. B aun, Eisai, Shi e, and UCB. M. Hol kamp
has ecei ed speake ’s hono a ia and/o consul ancy ees om
Cybe onics, Desi in, Eisai, GlaxoSmi hKline, Janssen-Cilag, UCB, and
Vi oPha ma. V. Villanue a has pa icipa ed in ad iso y boa ds and
pha maceu ical indus y sponso ed symposia o Eisai, UCB Pha ma,
Me ck Sha p & Dohme, Bial, P ize , GlaxoSmi hKline, Es e e,
No a is, Med onic, and Cybe onics. J. Pel ola has pa icipa ed in
clinical ials o Eisai, UCB, and Bial; ecei ed esea ch g an s om
Eisai, Med onic, UCB and Cybe onics; ecei ed speake hono a ia
om Cybe onics, Eisai, Med onic, O ion Pha ma, and UCB; ecei ed
suppo o a el o cong esses om Cybe onics, Eisai, Med onic, and
UCB; and pa icipa ed in ad iso y boa ds o Cybe onics, Eisai, Med-
onic, UCB, and P ize . In 2015–2016, E. Ben-Menachem has been a
consul an o Bial, Eisai, UCB, and Abbo and has ecei ed esea ch
g an s om Bial, Eisai, and UCB. She is Edi o -in-Chie o Ac a
Neu ologica Scandina ica.
Open Access This a icle is dis ibu ed unde he e ms o he C ea i e
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bu ion, and ep oduc ion in any medium, p o ided you gi e app op ia e
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Re e ences
1. Zebinix
Ò
(2016) Summa y o p oduc cha ac e is ics. h p://www.
ema.eu opa.eu/docs/en_GB/documen _lib a y/EPAR_-_P oduc _
In o ma ion/human/000988/WC500047225.pd . Accessed 04 Oc
2016
J Neu ol (2017) 264:421–431 429
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