Tetrabenazine versus deutetrabenazine for Huntington's disease : twins or distant cousins?
Abstract
Background: Tetrabenazine is the only US Food and Drug Administration‐approved drug for Huntington's disease, and deutetrabenazine was recently tested against placebo. A switching‐trial from tetrabenazine to deutetrabenazine is underway, but no head‐to‐head, blinded, randomized controlled trial is planned. Using meta‐analytical methodology, the authors compared these molecules. Methods: RCTs comparing tetrabenazine or deutetrabenazine with placebo in Huntington's disease were searched. The authors assessed the Cochrane risk‐of‐bias tool, calculated indirect treatment comparisons, and applied the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) framework. Results: The evidence network for this report comprised 1 tetrabenazine trial and 1 deutetrabenazine trial, both against placebo. Risk of bias was moderate in both. Participants in the tetrabenazine and deutetrabenazine trials did not differ significantly on motor scores or adverse events. Depression and somnolence scales significantly favored deutetrabenazine. Conclusion: There is low‐quality evidence that tetrabenazine and deutetrabenazine do not differ in efficacy or safety. It is important to note that these results are likely to remain the only head‐to‐head comparison between these 2 compounds in Huntington's disease.
Full text
Te abenazine Ve sus Deu e abenazine o
Hun ing on’s Disease: Twins o Dis an
Cousins?
Filipe B. Rod igues, MD,
1,2,3,
* Gonc
ßalo S. Dua e, MD,
2,3
Jo~
ao Cos a, MD, PhD,
2,3,4,5
Joaquim J. Fe ei a, MD, PhD,
2,3,a
Edwa d J. Wild, MD, PhD
1,a
Abs ac : Backg ound: Te abenazine is he only US Food and D ug Adminis a ion-app o ed d ug o
Hun ing on’s disease, and deu e abenazine was ecen ly es ed agains placebo. A swi ching- ial om
e abenazine o deu e abenazine is unde way, bu no head- o-head, blinded, andomized con olled ial is
planned. Using me a-analy ical me hodology, he au ho s compa ed hese molecules.
Me hods: RCTs compa ing e abenazine o deu e abenazine wi h placebo in Hun ing on’s disease we e
sea ched. The au ho s assessed he Coch ane isk-o -bias ool, calcula ed indi ec ea men compa isons,
and applied he G ading o Recommenda ions Assessmen , De elopmen , and E alua ion (GRADE) amewo k.
Resul s: The e idence ne wo k o his epo comp ised 1 e abenazine ial and 1 deu e abenazine ial,
bo h agains placebo. Risk o bias was mode a e in bo h. Pa icipan s in he e abenazine and
deu e abenazine ials did no di e significan ly on mo o sco es o ad e se e en s. Dep ession and
somnolence scales significan ly a o ed deu e abenazine.
Conclusion: The e is low-quali y e idence ha e abenazine and deu e abenazine do no di e in e ficacy o
sa e y. I is impo an o no e ha hese esul s a e likely o emain he only head- o-head compa ison
be ween hese 2 compounds in Hun ing on’s disease.
Hun ing on’s disease (HD) is a he edi a y neu odegene a i e
condi ion cha ac e ized by p og essi e mo o , cogni i e, and
beha io al dys unc ion.
1
Te abenazine (TBZ) is he only US
Food and D ug Adminis a ion-app o ed d ug o cho ea in
HD, and is usually aken 3 imes daily. Al hough i was de el-
oped o ea psychosis, i was la e ound o ease hype kine ic
mo emen diso de s, including cho ea, ics, a di e dyskinesia,
and dys onia, al hough, in he Uni ed S a es, i is licensed only
o ea ing cho ea.
2
Unlike classical neu olep ics, his com-
pound deple es p esynap ic dopamine by blocking esicula
monoamine anspo e ype 2 (VMAT2).
3
Deu e abenazine
(DEU), a s uc u ally ela ed molecule wi h deu e ium (a hea y
hyd ogen iso ype) placed a key posi ions, was ecen ly es ed
success ully agains placebo.
4
Deu e a ion p olongs hal -li e,
educes me abolism a iabili y, and is p oposed o ansla e in o
less equen dosing, a lowe daily dose, and imp o ed ole abil-
i y. The FIRST-HD s udy (clinical ials.go iden i ie
NCT01795859) has been in e p e ed as o e ing suppo o
simila e icacy o DEU wi h espec o TBZ, bu wi h ewe
ad e se e ec s and easie dosing.
5
An unmasked swi ching
design ial om TBZ o DEU (ARC-HD; clinical ials.go
iden i ie NCT01897896) is unde way, bu no head- o-head,
1
Hun ing on’s Disease Cen e , Ins i u e o Neu ology, Uni e si y College London, London, Uni ed Kingdom;
2
Labo a o y o Clinical Pha macology
and The apeu ics, Facul y o Medicine, Uni e si y o Lisbon, Lisbon, Po ugal;
3
Clinical Pha macology Uni , Ins i u o de Medicina Molecula , Lisbon,
Po ugal;
4
Coch ane Mo emen Diso de s G oup, Facul y o Medicine, Uni e si y o Lisbon, Lisbon, Po ugal;
5
Cen e o E idence-Based Medicine,
Facul y o Medicine, Uni e si y o Lisbon, Lisbon, Po ugal
*Co espondence o: D . Filipe B. Rod igues, Hun ing on’s Disease Cen e, Russell Squa e 10-12, London WC1B 5EH, UK; E-mail: . od igues@
ucl.ac.uk
Keywo ds: deu e abenazine, Hun ing on’s disease, indi ec compa ison, me a-analysis, e abenazine.
a
Joaquim J. Fe ei a and Edwa d J. Wild con ibu ed equally o his a icle.
Rele an disclosu es and con lic s o in e es a e lis ed a he end o his a icle.
This is an open access a icle unde he e ms o he C ea i e Commons A ibu ion License, which pe mi s use, dis ibu ion and
ep oduc ion in any medium, p o ided he o iginal wo k is p ope ly ci ed.
Recei ed 12 Decembe 2016; e ised 25 Janua y 2017; accep ed 12 Feb ua y 2017.
Published online 29 Ma ch 2017 in Wiley In e Science (www.in e science.wiley.com). DOI:10.1002/mdc3.12483
©2017 The Au ho s. Mo emen Diso de s Clinical P ac ice published by Wiley Pe iodicals, Inc. on behal o In e na ional Pa kin-
son and Mo emen Diso de Socie y.
582
RESEARCH ARTICLE
CLINICAL PRACTICE
blinded, andomized ial is planned. The e o e, we se ou o
compa e TBZ and DEU indi ec ly using me a-analysis
me hodology.
Ma e ials and Me hods
Ou s udy p o ocol was egis e ed (PROSPERO
CRD42016049199) ollowing he PRISMA-NMA amewo k.
6
We included andomized con olled ials ha compa ed TBZ
o DEU wi h placebo in pa ien s wi h HD. The ollowing ou -
come domains we e s udied: mo o , dep ession, somnolence,
and ad e se e en s (AEs). Se e e AEs (SAEs) we e classi ied
acco ding o he p ima y s udies, al hough nei he epo ed a
o mal de ini ion o an SAE. Re e ences we e sea ched in he
MEDLINE, Embase, an SAE and CENTRAL da abases, he
combining (Hun ing on) wi h ( e abenazine OR deu e a-
benazine) and applying he Coch ane Highly Sensi i e Sea ch
S a egy o iden i ying andomized ials. S udies we e e alu-
a ed using he Coch ane isk-o -bias ool. S udy selec ion, da a
collec ion, and app aisal we e done independen ly in duplica e.
Con inuous and dicho omous a iables we e p esen ed as mean
di e ences (MDs) and odds a ios, espec i ely, bo h wi h 95%
con idence in e als (95% CIs). Indi ec ea men compa ison
me a-analyses be ween TBZ and DEU we e calcula ed based
on a common compa a o using he Buche me hod.
7
Con idence in cumula i e e idence was assessed using he G ad-
ing o Recommenda ions Assessmen , De elopmen , and E alua-
ion (GRADE) Wo king G oup guidelines.
8
These comp ise a
widely endo sed ool o assess he quali y o s udies con ibu ing o
me a- esea ch ha akes in o accoun he domains: isk o bias,
inconsis ency, indi ec ness, imp ecision, and publica ion bias, and
classi ies e idence om high o e y low quali y, as ollows:
•High quali y: We a e e y con iden ha he ue e ec lies
close o ha o he es ima e o he e ec ;
•Mode a e quali y: We a e mode a ely con iden in he e ec
es ima e; he ue e ec is likely o be close o he es ima e o
he e ec , bu he e is a possibili y ha i is subs an ially di e -
en ;
•Low quali y: Ou con idence in he e ec es ima e is limi ed;
he ue e ec may be subs an ially di e en om he es ima e
o he e ec ; and
•Ve y low quali y: We ha e e y li le con idence in he e ec
es ima e; he ue e ec is likely o be subs an ially di e en
om he es ima e o e ec .
A sample-size calcula ion o a 1:1, pa allel equi alence ial
was calcula ed using S a a 14.0 so wa e (Aus in, Texas) assum-
ing 80% powe , 10% d opou , 0.05 alpha, a s anda d de ia ion
o 3.5 poin s on he Uni ied Hun ing on’s Disease Ra ing Scale
(UHDRS) cho ea subscale sco e, and 20% ma gin o equi a-
lence o TBZ e ec (5 UHDRS cho ea sco e poin s).
9
Resul s
In o al, 131 e e ences we e e ie ed, and 2 s udies we e
included.
4,9
Ou e idence ne wo k, desc ibing how he
included s udies ela ed o one ano he , comp ised 1 ial ha
es ed TBZ (TETRA-HD; n =84) and ano he ha es ed
DEU (FIRST-HD; n =90), bo h agains placebo (Fig. 1A).
The o e all isk o bias was mode a e in bo h s udies because o
a i ion and epo ing bias (Fig. 1B). In he TBZ a m o
TETRA-HD, p opo ionally mo e pa icipan s wi hd ew om
he s udy han in he placebo a m; and, in bo h s udies, se e al
impo an ou come measu es, such as quali y o li e, we e miss-
ing. In o he espec s ( andom sequence gene a ion, alloca ion
concealmen , blinding o pa ien and pa icipan s, blinding o
ou come assessmen s, and incomple e ou come da a o he
DEU ial), he s udies we e a low isk o bias.
A e a de ailed e iew o he me hodologies and ial popu-
la ions, we conside ed ha he included s udies we e me hod-
ologically and clinically simila and compa able on e ec
modi ie s, con i ming he ansi i i y assump ion needed o cal-
cula e an unbiased, indi ec es ima e o TBZ e sus DEU.
Bo h TBZ and DEU had a mild e ec on cho ea e sus pla-
cebo (5.0 and 4.4 poin imp o emen in he UHDRS cho ea
sco e, espec i ely) and did no di e signi ican ly on UHDRS
he cho ea sco e (MD 1.00; 95% CI 3.04, 1.04) o he o al
mo o sco e (MD 0.70; 95% CI 3.72, 5.12) (Table 1).
Dep ession and somnolence, which we e e alua ed using a ing
scales, a o ed DEU signi ican ly o e TBZ in bo h clinical
domains (MD 0.94; 95% CI 0.88–1.00; and MD 2.10; 95% CI
0.08–4.12, espec i ely) (Table 1). The odds o speci ic AEs did
no di e signi ican ly be ween in e en ions (Table 2). The
equi ed sample size calcula ed o a 1:1, pa allel, head- o-head
equi alence ial o TBZ e sus DEU was 608 pa icipan s.
Discussion
Ou indi ec compa ison, as assessed acco ding o he GRADE
amewo k, shows ha he e is low-quali y e idence ha TBZ
and DEU do no di e in e icacy and sa e y. DEU appea s sig-
ni ican ly less p one o dep essi e symp oms and somnolence,
bu his obse a ion, which was d awn om indi ec analysis o
a es ic ed e idence ne wo k, equi es alida ion in a di ec ,
sui ably designed ial.
Ou analysis mus be in e p e ed wi h cau ion o e all,
because indi ec compa isons only p o ide obse a ional e i-
dence: he powe o hypo hesis es ing elies on be ween-s udy
he e ogenei y, which hank ully was minimal in his case. Fu -
he mo e, he powe o ou compu a ion is limi ed by he e i-
dence ne wo k sample size.
10
I DEU ecei es licensing au ho iza ion, hen long- e m,
phase 4 s udies and eal-wo ld p ac ice will p o ide u he
in o ma ion on he clinical u ili y o DEU. None heless, ou
analysis aises conce ns o in o med clinical decision making in
HD: no clinical ial has ec ui ed o e 600 pa icipan s; and, o
ou knowledge, only 1 ongoing ial seeks o compa e TBZ
and DEU di ec ly: ARC-HD, whose non andomized, open-
label, swi ching design ca ies a isk o selec ion, de ec ion, and
pe o mance bias. The e o e, he p esen s udy seems likely o
emain he only easible and ealis ic, blinded, head- o-head
compa ison be ween TBZ and DEU in HD.
MOVEMENT DISORDERS CLINICAL PRACTICE 583
doi:10.1002/mdc3.12483
F.B. Rod igues e al. RESEARCH ARTICLE
Au ho Roles
1. Resea ch P ojec : A. Concep ion, B. O ganiza ion, C. Exe-
cu ion; 2. S a is ical Analysis: A. Design, B. Execu ion, C.
Re iew and C i ique; 3. Manusc ip P epa a ion: A. W i ing
he Fi s D a , B. Re iew and C i ique.
F.B.R.: 1A, 1B, 1C, 2A, 2B, 3A
J.J.F.: 1A, 3B
Figu e 1 A: Indi ec compa ison model and (B) he isk o bias in sou ce s udies. Wi h 1 o 2 o 6 domains a high isk o bias, he o e -
all isk o bias o each o hese s udies was classified as mode a e. TBZ, e abenazine; DEU, deu e abenazine.
TABLE 1 Ou comes o di ec and indi ec compa isons
Ou come Mean di e ence (95% CI)
Di ec compa isons
a
Indi ec compa isons
b
TBZ-placebo DEU-placebo TBZ-DEU
UHDRS cho ea sco e 3.5 (5.2, 1.9)
c
2.5 (3.7, 1.3)
d
1.00 (3.04, 1.04)
UHDRS o al mo o sco e 3.3 (7.0, 0.3) 4.0 (6.5, 1.5)
d
0.70 (3.72, 5.12)
Dep ession scale 0.76 (0.71, 0.81)
e
0.18 (0.22, 0.14)
d
0.94 (0.88, 1.00)
d
Epwo h Sleepiness Scale 1.8 (0.3, 3.4)
e
0.3 (1.6, 1.0)
d
2.10 (0.08, 4.12)
d
CI, confidence in e al; TBZ, e abenazine; DEU, deu e abenazine; UHDRS, Unified Hun ing on’s Disease Ra ing Scale.
a
Fo di ec compa isons, he alues p esen ed a e he di e ence be ween ac i e ea men and placebo in he mean change in sco e
epo ed in each indi idual s udy. In each case, posi i e alues a e in a o o placebo, and nega i e alues a e in a o o ac i e ea men .
b
Fo indi ec compa isons, he alues ep esen he di e ence be ween TBZ and DEU in he mean change in sco e. He e, posi i e alues a e
in a o o DEU, and nega i e alues a e in a o o TBZ. In he TBZ s udy, UHDRS cho ea sco es we e adjus ed o baseline alues and si e,
and dep ession was summa ized using he Hedges g e ec size om he Hamil on Dep ession Scale. In he DEU s udy, UHDRS cho ea
sco es we e adjus ed o baseline alues only, and dep ession was summa ized using he Hedges g e ec size om he Hospi al and Anxie y
Dep ession Scale dep ession subscale.
c
Significan ly a o s TBZ.
d
Significan ly a o s DEU.
e
Significan ly a o s placebo.
TABLE 2 Ad e se e en s o di ec and indi ec compa isons
Ad e se e en Odds a io (95% CI)
a
Di ec compa isons
b
Indi ec compa isons
c
TBZ-placebo DEU-placebo TBZ-DEU
Se ious ad e se e en s,
as defined by s udy au ho s
5.44 (0.28, 104.49) 1.00 (0.06, 16.50) 5.44 (0.09, 322.08)
Somnolence 13.32 (1.67, 106.07)
d
2.69 (0.49, 14.64) 4.95 (0.34, 72.37)
Dia hea 0.72 (0.15, 3.46) 9.87 (0.52, 188.88) 0.07 (0.03, 2.06)
Insomnia 21.84 (1.25, 380.62)
d
1.54 (0.24, 9.66) 14.18 (0.47, 426.77)
Fa igue 1.86 (0.54, 6.37) 1.54 (0.24, 9.66) 1.21 (0.31, 11.14)
Falls 1.30 (0.36, 4.64) 0.48 (0.08, 2.74) 2.71 (0.31, 23.98)
Dep ession 11.15 (0.62, 200.33) 0.65 (0.10, 4.10) 17.15 (0.55, 531.90)
CI, confidence in e al; TBZ, e abenazine; DEU, deu e abenazine.
a
All alues a e odds a ios wi h 95% CIs in pa en heses, wi h 1 indica ing absence o di e ence. CIs no spanning 1 indica e a s a is ically sig-
nifican ly al e ed odds.
b
Fo di ec compa isons, alues g ea e han 1 indica e an inc eased odds in he ac i e ea men a m.
c
Fo indi ec compa isons, alues g ea e han 1 indica e an inc eased odds o TBZ.
d
Significan ly a o s placebo.
584 MOVEMENT DISORDERS CLINICAL PRACTICE
doi:10.1002/mdc3.12483
Te abenazine Ve sus Deu e abenazine o HD
RESEARCH ARTICLE
E.J.W.: 1A, 3B
G.S.D.: 1B, 1C, 2B
J.C.: 2C, 3B
Disclosu es
E hical Compliance S a emen : We con i m ha we ha e
ead he Jou nal’s posi ion on issues in ol ed in e hical publica-
ion and a i m ha his wo k is consis en wi h hose guidelines.
Funding Sou ces and Con lic o In e es : Filipe B. Rod i-
gues, Joaquim J. Fe ei a, and Edwa d J. Wild a e in es iga o s
on a TEVA-sponso ed ial o ano he d ug, laquinimod. None
ha e ecei ed any pe sonal paymen s o sala y con ibu ions o
his wo k, no ha e hey been in ol ed in any TEVA-spon-
so ed ial o p idopidine. Filipe B. Rod igues, Joaquim J. Fe -
ei a, and Edwa d J. Wild a e suppo ed by CHDI Founda ion.
Joaquim J. Fe ei a ecei ed esea ch unds om GlaxoSmi hK-
line, G unen hal, Fundac
ß
~ao MSD (Po ugal), TEVA, MSD,
Alle gan, Ipsen, No a is, Med onic. Edwa d J. Wild is sup-
po ed by he Medical Resea ch Council and ecei ed esea ch
unds om GlaxoSmi hKline Founda ion. Filipe B. Rod igues
and Gonc
ßalo S. Dua e a e ex e nal edi o s o he Coch ane
Mo emen Diso de s G oup, and Jo~ao Cos a is he edi o o
Coch ane Mo emen Diso de s G oup.
Financial disclosu es o he p e ious 12 mon hs: Joaquim
J. Fe ei a has speake and consul an ela ionships wi h
GlaxoSmi hKline, No a is, TEVA, Lundbeck, Sol ay, Abbo ,
BIAL, Me ck-Se ono, Me z, Ipsen, Biogen, and Suno ion
Pha maceu icals, none o which has a known, speci ic in e es
in he submi ed wo k. Edwa d J. Wild has pa icipa ed in
scien i ic ad iso y boa ds wi h Ho mann-La Roche L d., Ionis,
Shi e, GlaxoSmi hKline, and Wa e Li e Sciences. All hono a ia
we e paid h ough UCL Consul an s L d., a wholly owned sub-
sidia y o UCL. Filipe B. Rod igues, Gonc
ßalo S. Dua e, and
Jo~ao Cos a epo ed no sou ces o unding and no con lic s o
in e es .
Re e ences
1. Ba es GP, Do sey R, Gusella JF, e al. Hun ing on disease [se ial
online]. Na Re Dis P ime s 2015;1:15005.
2. Kau N, Kuma P, Jamwal S, Deshmukh R, Gau am V. Te abenazine:
spo ligh on d ug e iew. Ann Neu osci 2016;23:176–185.
3. Janko ic J. Dopamine deple e s in he ea men o hype kine ic mo e-
men diso de s. Expe Opin Pha maco he 2016;17:2461–2470.
4. Hun ing on S udy G oup, F ank S, Tes a CM, e al. E ec o deu e a-
benazine on cho ea among pa ien s wi h Hun ing on disease: a andom-
ized clinical ial. JAMA 2016;316:40–50.
5. Reilmann R. Deu e abenazine-no a e olu ion bu welcome e olu ion
o ea ing cho ea in Hun ing on disease. JAMA Neu ol 2016;73:1404–
1406.
6. Hu on B, Salan i G, Caldwell DM, e al. The PRISMA ex ension
s a emen o epo ing o sys ema ic e iews inco po a ing ne wo k
me a-analyses o heal h ca e in e en ions: checklis and explana ions.
Ann In e n Med 2015;162:777–784.
7. Buche HC, Guya GH, G i i h LE, Wal e SD. The esul s o di ec
and indi ec ea men compa isons in me a-analysis o andomized con-
olled ials. J Clin Epidemiol 1997;50:683–691.
8. Guya GH, Oxman AD, Schunemann HJ, Tugwell P, Kno ne us A.
GRADE guidelines: a new se ies o a icles in he Jou nal o Clinical
Epidemiology. J Clin Epidemiol 2011;64:380–382.
9. Hun ing on S udy G oup. Te abenazine as an icho ea he apy in Hun -
ing on disease: a andomized con olled ial. Neu ology 2006;66:366–
372.
10. Mills EJ, Ghemen I, O’Regan C, Tho lund K. Es ima ing he powe
o indi ec compa isons: a simula ion s udy [se ial online]. PLoS One
2011;6:e16237.
MOVEMENT DISORDERS CLINICAL PRACTICE 585
doi:10.1002/mdc3.12483
F.B. Rod igues e al. RESEARCH ARTICLE