Oral vs. outpatient parenteral antimicrobial treatment for infective endocarditis: study protocol for the spanish oralPAT‑IE GAMES Trial

Vol.:(0123456789)
In ec Dis The (2025) 14:643–655
h ps://doi.o g/10.1007/s40121-025-01110-9
STUDY PROTOCOL
O al s. Ou pa ien Pa en e al An imic obial
T ea men o In ec i e Endoca di is: S udy P o ocol
o  heSpanish O aPAT‑IE GAMES T ial
Guille moCue o · Ma aHe nández‑Meneses· A ís idesdeAla cón· Ra aelLuque‑Ma quez·
Ma íaM.Alonso‑Socas· AnaLópez‑Li ola· Víc o González‑Ramallo· AneJ.Goikoe xea‑Agi e· Da idNicolás·
MiguelA.Goenaga· Espe anzaMe ino · F ancescEsc ihuela‑Vidal· Pila Ma ín‑Dá ila· BelénLoeches·
LucíaBoix‑Palop· O iolGasch· Ma aCamp ecios· AliciaHe nández‑To es· La aGa cía‑Ál a ez·
Ma cosPaja ón· Ma íaAngelsRibas· RosaBlanes‑He nández· InmaculadaLópez‑Mon esinos·
LuisE.López‑Co és· Bá ba aVidal· Ma ianaFe nández‑Pi ol· Dolo esNa a o· AsunciónMo eno·
Co alSala· JuanAmb osioni· JoséM.Mi ó· O aPAT‑IE GAMES In es iga o s
Recei ed: Oc obe 30, 2024 / Accep ed: Janua y 23, 2025 / Published online: Ma ch 1, 2025
© The Au ho (s) 2025
ABSTRACT
In oduc ion: The POET ial demons a ed
ha mo ing om in a enous o o al an ibio ics
in s able pa ien s wi h le ‑sided in ec i e endo‑
ca di is (IE) was nonin e io o ully pa en e al
ea men . Howe e , i did no compa e ou pa‑
ien s a egies.
Me hods: The O aPAT‑IE GAMES ial is a non‑
in e io i y, mul icen e , andomized, open‑label
s udy aimed o compa e pa ial o al e sus ou ‑
pa ien pa en e al an ibio ic he apy (OPAT) o
consolida ion o an ibio ic ea men in le ‑
sided IE. A o al o 342 s able pa ien s wi h IE
caused by selec ed mic o‑o ganisms will e en‑
ually be included. A e a minimum o 10
days o pa en e al ea men , s able pa ien s
D . José M. Mi ó is membe o he Reial Academia de
Medicina de Ca alunya (RAMC), Ba celona, Spain.
P io P esen a ion: The O aPAT‑IE GAMES ial opened
i s i s si e o ec ui men in Ap il 2022. The i s
pa ien was en olled in Augus 2022. P elimina y da a
on pa ien ec ui men o his s udy we e p esen ed
in pos e o ma a he 17 h In e na ional Socie y o
In ec ious Ca dio ascula Diseases (ISCVID) Symposium
held in June 16–18, 2024, in Malmö, Sweden; and as an
o al p esen a ion a he 13 h Cong ess o he Sociedad
Española de In ecciones Ca dio ascula es (SEICAV) held
in No embe 22–23, 2024 in Bilbao, Spain. The abs ac
p esen ed a bo h con e ences (wi h upda ed p elimina y
ec ui men da a) can be seen as Appendix C o he
supplemen a y ma e ial. The ec ui men pe iod has
been ex ended un il he end o 2026.
O aPAT‑IE GAMES In es iga o s a e lis ed in
acknowledgemen s sec ion.
Supplemen a y In o ma ion The online e sion
con ains supplemen a y ma e ial a ailable a
h ps:// doi. o g/ 10. 1007/ s40121‑ 025‑ 01110‑9.
G.Cue o(*)· M.He nández‑Meneses· A.Mo eno·
C.Sala· J.Amb osioni(*)· J.M.Mi ó
In ec ious Diseases Depa men , Hospi al
Clinic‑IDIBAPS, Uni e si y o Ba celona, Villa oel
170, 08036Ba celona, Spain
e‑mail: [email p o ec ed]
J. Amb osioni
e‑mail: [email p o ec ed]
M. He nández‑Meneses
e‑mail: [email p o ec ed]
A. Mo eno
e‑mail: [email p o ec ed]
C. Sala
e‑mail: [email p o ec ed]
644
In ec Dis The (2025) 14:643–655
a e andomized o o al he apy o OPAT. The
p ima y end‑poin is a composi e o all‑cause
mo ali y, unplanned ca diac su ge y, elapse
o posi i e blood cul u es and/o unplanned
hospi al admission. Pa ien s a e ollowed‑up o
6mon hs a e comple ing an ibio ic he apy.
Planned Ou come: This ial seeks o demon‑
s a e he equi alen e icacy o he wo ou ‑
pa ien s a egies cu en ly a ailable o s able
pa ien s wi h IE in he consolida ion phase o
an ibio ic ea men .
Conclusion: In a global con ex o limi ed
heal hca e esou ces and a sus ained inc ease in
elde ly and ail pa ien s, i is o g ea impo ‑
ance o demons a e he e ec i eness and
sa e y o ou pa ien managemen s a egies ha
could educe he du a ion o con en ional hos‑
pi aliza ions wi h hei po en ial complica ions
and inhe en cos s.
T ial Regis a ion: Eud aCT: 2020‑001024‑34.
ClinicalT ials.go iden i ie : NCT05398679.
J. M. Mi ó
e‑mail: [email p o ec ed]
G.Cue o· A.deAla cón· P.Ma ín‑Dá ila·
I.López‑Mon esinos· L.E.López‑Co és·
J.Amb osioni· J.M.Mi ó
CIBERINFEC, Ins i u o de Salud Ca los III, Mad id,
Spain
e‑mail: [email p o ec ed]
P. Ma ín‑Dá ila
e‑mail: [email p o ec ed]
I. López‑Mon esinos
e‑mail: ilopezmon esinos@hma .ca
L. E. López‑Co és
e‑mail: [email p o ec ed]
A.deAla cón· R.Luque‑Ma quez· D.Na a o
Clinical Uni o In ec ious Diseases, Mic obiology
andPa asi ology (UCEIMP), Ins i u e o Biomedicine
o Se ille (IBiS), Vi gen del Rocío Uni e si y
Hospi al/CSIC/Uni e si y o Se ille, Se ille, Spain
e‑mail: [email p o ec ed]
D. Na a o
e‑mail: [email p o ec ed]
M.M.Alonso‑Socas· A.López‑Li ola
Hospi al Uni e si a io de Cana ias, Tene i e, Spain
e‑mail: [email p o ec ed]
A. López‑Li ola
e‑mail: [email p o ec ed]
V.González‑Ramallo
Hospi al Gene al Uni e si a io G ego io Ma añón,
Mad id, Spain
e‑mail: [email p o ec ed]
A.J.Goikoe xea‑Agi e
Hospi al Uni e si a io de C uces, Bilbao, Spain
e‑mail: [email p o ec ed]
D.Nicolás
In e nal Medicine‑Home Hospi aliza ion Uni ,
Hospi al Clinic‑IDIBAPS, Uni e si y o Ba celona,
Ba celona, Spain
e‑mail: [email p o ec ed]
M.A.Goenaga
Hospi al Uni e si a io Donos i, Ins i u o
In es igación Biogipuzkoa, SanSebas ián, Spain
e‑mail: [email p o ec ed]
E.Me ino
Uni o In ec ious Diseases, Alican e Gene al
Uni e si y Hospi al ‑ Alican e Ins i u e o Heal h
andBiomedical Resea ch (ISABIAL), Alican e, Spain
e‑mail: [email p o ec ed]
E.Me ino
Clinical Medicine Depa men , Miguel He nández
Uni e si y, Elche, Spain
F.Esc ihuela‑Vidal
Hospi al Uni e si a io de Bell i ge, Ba celona, Spain
e‑mail: [email p o ec ed]
P.Ma ín‑Dá ila
Hospi al Uni e si a io Ramón y Cajal, Ins i u o
Ramón y Cajal de In es igación Sani a ia (IRYCIS),
Mad id, Spain
B.Loeches
Hospi al Uni e si a io La Paz, Mad id, Spain
e‑mail: [email p o ec ed]
L.Boix‑Palop
Hospi al Mu ua de Te assa, Te assa, Spain
e‑mail: [email p o ec ed]
O.Gasch
Se ei de Malal ies In eccioses, Hospi al Uni e si a i
Pa c Taulí, Ins i u d’In es igació i Inno ació Pa c
Taulí (I3PT‑CERCA), Uni e si a Au ònoma de
Ba celona, Sabadell, Spain
e‑mail: [email p o ec ed]
M.Camp ecios
Hospi al de la San a C eu y San Pau, Ba celona,
Spain
e‑mail: [email p o ec ed]
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In ec Dis The (2025) 14:643–655
Keywo ds: Randomized con olled ial;
In ec i e endoca di is; Mo ali y; O al an ibio ic
he apy; O al s ep‑down an ibio ic ea men ;
Pa ial o al ea men ; OPAT; Ou pa ien pa en e al
an ibio ic ea men ; Rein ec ions; Relapses
Key Summa y Poin s
The O aPAT‑IE GAMES is he i s andomized
clinical ial o compa e he wo ou pa ien
s a egies a ailable o pa ien s wi h s able
in ec i e endoca di is in he consolida ion
phase o an ibio ic ea men .
Al hough he planned sample size is la ge
(n=342), i will be ca ied ou in 20 hospi als
wi hin he mul icen e and mul idiscipli‑
na y GAMES s udy g oup, so i is conside ed
easible.
This s udy will p esumably sha e he inhe ‑
en limi a ions o i s open label design. Fu ‑
he mo e, he ial will e alua e o al e sus
pa en e al an ibio ic he apy s a egies bu
will no be powe ed o demons a e di e ‑
ences be ween a ious subg oups o IE (e.g.,
na i e al e IE, p os he ic al e IE, speci ic
mic o‑o ganisms, e c.).
Beyond he a o emen ioned limi a ions, his
s udy could ha e a ele an impac on clini‑
cal p ac ice, imp o ing he quali y o li e o
pa ien s and allowing he sho ening o con‑
en ional hospi aliza ions wi h hei inhe en
complica ions and cos s.
INTRODUCTION
Al hough in ec i e endoca di is (IE) is a a e
in ec ious disease, wi h c ude annual inci‑
dence a es anging be ween 1.5 and 9.0 cases
pe 100,000 people, mo ali y has emained
ela i ely s able a a ound 20% du ing hospi‑
aliza ion, and mo e han 30% pe yea [1]. In
Spain, he c ude annual incidence is es ima ed
a a ound 3 cases pe 100,000 people, showing
a sligh bu cons an inc ease [2]. This incidence
ep esen s app oxima ely 1600 new cases o IE
pe yea in ou coun y.
Some classic ecommenda ions o he ea ‑
men o IE ha e emained s able and alid o
decades. These include: (1) he need o p o‑
longed an imic obial he apy (4–6 weeks); (2)
A.He nández‑To es
Hospi al Vi gen de la A ixaca, Mu cia, Spain
e‑mail: [email p o ec ed]
L.Ga cía‑Ál a ez
Hospi al San Ped o‑CIBIR, Log oño, Spain
e‑mail: [email p o ec ed]
M.Paja ón
Hospi al Ma qués de Valdecilla, San ande , Spain
e‑mail: [email p o ec ed]
M.A.Ribas
Hospi al Son Espases, Palma, Spain
e‑mail: [email p o ec ed]
R.Blanes‑He nández
Hospi al de La Fe, Valencia, Spain
e‑mail: [email p o ec ed]
I.López‑Mon esinos
Hospi al del Ma , Ba celona, Spain
L.E.López‑Co és
Unidad Clínica de En e medades In ecciosas y
Mic obiología, Hospi al Uni e si a io Vi gen
Maca ena, Se ille, Spain
L.E.López‑Co és
Depa amen os de Medicina y Mic obiología,
Facul ad de Medicina, Uni e sidad de Se illa,
Se ille, Spain
L.E.López‑Co és
Ins i u o de Biomedicina de Se illa (IBiS)/CSIC,
Se ille, Spain
B.Vidal
Ca diology Depa men , Hospi al Clinic‑IDIBAPS,
Uni e si y o Ba celona, Ba celona, Spain
e‑mail: [email p o ec ed]
M.Fe nández‑Pi ol
Mic obiology Depa men , Hospi al Clinic‑IDIBAPS,
Uni e si y o Ba celona, Ba celona, Spain
e‑mail: [email p o ec ed]
646
In ec Dis The (2025) 14:643–655
pa en e al adminis a ion; (3) wi h bac e icidal
an imic obials; and (4) in hospi alized pa ien s,
gi en he high complexi y o i s managemen .
In ac , all hese ecommenda ions a e s ill
alid in he mos ecen Ame ican and Eu o‑
pean guidelines [3, 4]. Howe e , he need o a
p olonged hospi al s ay p edisposes pa ien s o
nosocomial complica ions, such as coloniza ion
wi h esis an mic obiological lo a and noso‑
comial in ec ions, and, u he mo e, i s associa‑
ion wi h a ma ked de e io a ion in unc ional
s a us has been obse ed in ge ia ic pa ien s
[5]. Addi ionally, his inc eases cos s and limi s
he a ailabili y o beds o pa ien s in e ia y
cen e s. Ou pa ien pa en e al an ibio ic he apy
(OPAT) has been shown o be e ec i e and sa e
o he ea men o in ec i e endoca di is (IE)
in selec ed cases [6–11]. Howe e , un il ecen ly,
mos in ec ious disease guidelines had es ic i e
c i e ia o OPAT o his disease. In a wo k pub‑
lished by he GAMES g oup (G upo de Apoyo
al Manejo de la Endoca di is en España), i was
concluded ha hese ecommenda ions could be
g ea ly expanded [12].
On he o he hand, a pa en e al ou e can be
a sou ce o se ious complica ions (e.g., h om‑
bosis o bac e emia). Addi ionally, in a enous
an ibio ics a e gene ally expensi e. O al an ibi‑
o ic he apy could educe hese complica ions
and be an app op ia e al e na i e, bu expe i‑
ence wi h le ‑sided endoca di is was limi ed o
small se ies and coho s udies [13]. The la ge
POET andomized clinical ial published in
2019 demons a ed ha a signi ican p opo ‑
ion o pa ien s wi h le ‑sided IE could bene i
om o al an ibio ic he apy, wi h e icacy and
sa e y compa able o pa en e al ea men [14].
In his ial, howe e , all pa ien s in he pa en‑
e al a m and mos o hose included in he o al
a m, comple ed hei ea men egimens in con‑
en ional hospi aliza ion. To da e, no ial has
compa ed he e icacy and sa e y o OPAT e sus
ou pa ien o al he apy o his g oup o well‑
selec ed pa ien s.
The O aPAT‑IE GAMES ial (ClinicalT ials.
go ID: NCT05398679), cu en ly ec ui ing,
may p o ide he necessa y e idence o choose
one modali y o e ano he and o iden i y spe‑
ci ic g oups ha may bene i mo e om one o
hese s a egies. We aimed o demons a e he
non‑in e io i y o o al ou pa ien an ibio ic
he apy in compa ison wi h OPAT. As second‑
a y objec i es, we will compa e he quali y o
li e o pa ien s included in bo h a ms, he cos s
o in e en ions h ough a pha maco‑economic
sub‑s udy, and he complica ions ela ed o pa ‑
en e al and o al adminis a ion o an ibio ics
(such as an ibio ics o ca he e ‑ ela ed ad e se
e en s and supe in ec ions, e.g., Clos idioides
di icile dia hea).
METHODS
S udy Design
The O aPAT‑IE GAMES s udy is a na ionwide,
nonin e io i y, mul icen e , p ospec i e, and‑
omized, con olled, open, non‑in e io i y (del a
10%) clinical ial. Randomiza ion will be done
1:1 and will be pe o med online h ough a cen‑
alized compu e sys em.
Eligible Pa ien s
Pa ien s included in he s udy mus mee all he
ollowing inclusion c i e ia: (1) le ‑sided na i e
o p os he ic de ini e in ec i e endoca di is
based on he modi ied Duke c i e ia in ec ed
wi h one o he ollowing non‑ esis an mic o‑
o ganisms: non‑ esis an s ep ococci and o he
G am posi i e cocci, e.g., G anulica ella and
Abio ophia, En e ococcus aecalis, S aphylococ-
cus au eus, coagulase‑nega i e s aphylococci,
and HACEK g oup (Haemophilus spp., Agg ega i-
bac e spp., Ca diobac e ium hominis, Eikenella
co odens, and Kingella spp); (2)≥18 yea s old;
(3)≥10 days o app op ia e pa en e al an ibi‑
o ic ea men o e all and a leas 1week o
app op ia e pa en e al ea men a e al e
su ge y (a posi i e al e cul u e change he
o e all du a ion o ea men , bu no a ec ing
he pa ien ’s eligibili y); (4) T<38.0°C o mo e
han 2days; (5) C‑ eac i e p o ein ha d opped
below 25% o he peak alue o below an abso‑
lu e alue o 20mg/L, and he whi e blood cell
coun d opped o less han 15× 109/L du ing
an ibio ic ea men ; (6) no sign o abscess o ‑
ma ion e ealed by echoca diog aphy; and (7)
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In ec Dis The (2025) 14:643–655
ans ho acic (TTE) and/o ansoesophageal
echoca diog aphy (TEE) pe o med p e e ably
wi hin 48 h o andomiza ion (TEE is no man‑
da o y i TTE is o good and eassu ing quali y).
Echoscopy (po able echoca diog ams) a e also
admi ed, as long as hey a e egis e ed on he
clinical his o y.
Exclusion C i e ia
(1) Body mass index>40; (2) concomi an in ec‑
ion equi ing in a enous an ibio ic he apy;
(3) inabili y o gi e in o med consen o pa ‑
icipa ion; (4) suspicion o educed abso p ion
o o al ea men due o abdominal diso de ;
(5) mic o‑o ganisms o he han hose de ined
in inclusion c i e ia; (6) any immunosupp es‑
si e disease o any medical condi ion a he
disc e ion o he in es iga o ha may p eclude
o al o OPAT he apy; (7) no amily o app op i‑
a e home suppo ; (8) educed compliance; (9)
women o childbea ing po en ial wi h a posi i e
p egnancy es , o pa icipan s (male o emale)
who wish o plan a p egnancy du ing he ial
pe iod; and (10) women in lac ancy pe iod.
Se ing
The s udy is being ca ied ou in 20 Spanish uni‑
e si y hospi als, coo dina ed by he Hospi al
Clinic de Ba celona: Hospi al de San Pau I la
San a C eu, Ba celona; Hospi al Uni e si a io de
Bell i ge, Ba celona; Hospi al Vi gen del Rocío,
Se illa; Hospi al Vi gen Maca ena, Se illa; Hos‑
pi al G ego io Ma añón, Mad id; Hospi al de
C uces, Bilbao; Hospi al de Donos ia, Guipuz‑
koa; Hospi al San Ped o, Log oño; Hospi al
Ma qués de Valdecilla, San ande ; Hospi al Uni‑
e si a io de Cana ias, Tene i e; Hospi al Son
Espases, Palma Mallo ca; Conso ci Sani a i Pa c
Taulí de Sabadell, Ba celona; Hospi al Gene al
Uni e si a io de Alican e, Alican e; Hospi al
Uni e si a io La Paz, Mad id; Hospi al Clínico
Uni e si a io Vi gen de la A ixaca, Mu cia; Hos‑
pi al Uni e si a io y Poli écnico La Fe, Valencia;
Hospi al Uni e si a i Mú ua Te assa, Te assa,
Ba celona; Hospi al Uni e si a io Ramón y Cajal,
Mad id; and Hospi al del Ma , Ba celona.
In e en ion
The ini ial pa en al IE ea men will be in
acco dance wi h he Eu opean guidelines [8].
Selec ed pa ien s (n=342) wi h le ‑side IE and
speci ic mic oo ganisms (S aphylococcus au eus,
coagulase nega i e s aphylococci, S ep ococcus
spp., En e ococcus spp., and o he selec ed mic o‑
o ganisms), and a ailable o al op ions will be
andomized 1:1 o inish an ibio ic he apy on
ei he ou pa ien pa en e al o o al egimens
(wi h wo ac i e o al d ugs; see Appendix A in
he supplemen a y ma e ial). Be o e andomi‑
za ion, pa ien s will ha e comple ed a leas
10days o in a enous he apy, and/o a e
7days in he case o ca diac al ula su ge y o
IE, and ha e shown good clinical e olu ion and
no clinical o echoca diog aphic signs o po en‑
ial bad p ognosis. A e andomiza ion, he
pa ien mus ollow he assigned ea men (o al
s. OPAT) o a leas 25% o he o al du a ion o
ea men o hei endoca di is. Pa en e al con‑
solida ion ea men in he OPAT egimen a m
will be selec ed a he disc e ion o he ea ing
physician and ollowing he ecommenda ions
o cu en clinical guidelines. I may consis o
con en ional an ibio ics o daily adminis a‑
ion as well as “long‑ac ing” op ions [4].
P ima y Endpoin
The composi e endpoin (wha e e happen i s )
consis s o unplanned hospi aliza ion due o any
eason, all‑cause mo ali y, unplanned ca diac
su ge y and IE elapse o posi i e blood cul u es
wi h he p ima y pa hogen wi hin 6mon hs
om diagnosis. Unplanned ca diac su ge y
is de ined as su ge y o he hea no planned
be o e andomiza ion. Su ge y due o s e ile
pe ica dial e usion o hemo hage is, howe e ,
no included in his endpoin . Seconda y end‑
poin s a e pa ien sa is ac ion (s anda dized
ques ionnai es), complica ions ela ed o pa ‑
en e al adminis a ion and o al adminis a ion
o an ibio ics,e.g., an ibio ic ad e se eac ions,

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In ec Dis The (2025) 14:643–655
ca he e ‑ ela ed ad e se e en s, e.g., phlebi is
and line‑ ela ed bloods eam in ec ions, and
supe in ec ions, e.g., Clos idioides di icile dia ‑
hea. Finally, also as a seconda y objec i e o his
ial, a cos –e icacy analysis will be conduc ed
o compa e heal hca e cos s in bo h s udy a ms.
Only di ec cos s will be included and he cos s
will be es ima ed om he Na ional heal h Sys‑
em pe spec i e. The cos s ha we will include
a e: s a , pha macy (d ugs and consumables),
anspo a ion o s a o pa ien s’ homes, diag‑
nos ic es s, s uc u al cos s, cos o ad e se
e en s and ca he e complica ions, eme gency
oom isi s, and hospi al eadmissions [15].
Follow‑Up
Pa ien s will be ollowed up o 6 mon hs a e
he cessa ion o an ibio ic ea men . Follow‑up
examina ions a 1 and 6 mon hs will include
clinical examina ions and measu emen o whi e
blood cell coun , C‑ eac i e p o ein, and blood
cul u es (Fig.1; and ial schedule in Table1).
The ollow‑up design is aimed o be as simila as
possible o no mal clinical p ac ice, eques ing
essen ial examina ions and lea ing i up o he
ea ing physicians o eques addi ional s udies
acco ding o each speci ic case. Follow‑up TTE
will also be eques ed acco ding o he c i e ia
o he ea ing physicians.
S a is ical Analysis Plan
The s a is ical analysis will be ca ied ou in
acco dance wi h he p inciples speci ied in he
In e na ional Con e ence on Ha moniza ion
(ICH) Topic E9 (CPMP/ICH/363/96). A de ailed
S a is ical Analysis Plan (SAP) ag eed upon by
he Sponso and he P ojec S a is ician will
be a ailable be o e he da abase closu e. This
SAP will ollow he gene al egula o y ecom‑
menda ions gi en in he ICHE9 guidance, as
well as o he speci ic guidance on me hodolog‑
ical and s a is ical issues. Also, i will s ick o
Fig. 1 S udy design. EOT end o ea men , IE in ec i e endoca di is, IV in a enous, m1 i s mon h o ollow-up, m3 hi d
mon h o ollow-up, OPAT ou pa ien pa en e al an ibio ic ea men , TOC es o cu e
649
In ec Dis The (2025) 14:643–655
Table 1 The O aPAT-IE GAMES isi schedule and s udy p ocedu es
Biochemis y will include a leas glycemia, ionog am, CRP, and c ea inine, and all o he de e mina ions a he disc e ion o
he in es iga o . Hema ology will include hema oc i , WBC coun wi h di e en ial coun and pla ele s, and all o he de e -
mina ions a he disc e ion o he in es iga o
a Will be aken a baseline and epea ed when clinically indica ed un il end o ea men (EOT). O he cul u es (u ine, spu-
um, e c.) may be conside ed a he disc e ion o he in es iga o
b Regula isi s a e pe iodical isi s, he isi pe iodici y being de ined as o pa ien s wi h pa en e al ea men , as daily isi s
o e e y 48h, wi h one en y pe week eco ded in he eCRD. Each cen e can o ganize isi s acco ding o i s usual p ac ice,
bu a leas one elephone con ol and one weekly ace- o- ace isi is sugges ed ( he la e mus be egis e ed in he eCRD),
un il he end o he s udy ea men
c When clinically indica ed by he in es iga o eam, a leas once weekly
Sc een
pe iod
Baseline Nu se egu-
la isi sb
EOT Mon h 1 Mon h 3 Mon h 6 Ea ly e -
mina ion
Eligibili y,
consen
signa u e
Pa en e al
an imi-
c obials
acco d-
ing o
inclusion
c i e ia
x
Randomiza-
ion
x
Full exam x
His o y,
exam and
sa e y
e alua ion
xxxxxxx
Demo-
g aphic
da a
x
Blood
cul u esa
x x x x x
Hema ology x xcxxxxx
Biochemis-
y
x xcxxxxx
P egnancy
es
x x x
Volume o
blood (mL)
20mL Up o 20mL Up o
20mL
Up o
20mL
Up o
20mL
Up o
20mL
Up o
20mL
To al olume
o blood
(mL)
650
In ec Dis The (2025) 14:643–655
he ecommenda ions gi en by he consensus
documen s o he scien i ic jou nals o imp o e
he eliabili y and alue o medical esea ch li ‑
e a u e by p omo ing anspa en and accu a e
epo ing o clinical esea ch s udies.
The SAS Sys em (Release 9.4, o an upg aded
e sion), o equi alen alida ed s a is ical so ‑
wa e, will be he s a is ical so wa e used o
analyze he da ase s. A summa y o he o e all
app oach o s a is ical analysis is p esen ed he e‑
a e . The ial is designed as a non‑in e io i y
ial, and hence o de e mine whe he pa ial
o al ea men is non‑in e io o OPAT. Acco d‑
ing o ou own a es o he p ima y endpoin ,
unplanned hospi aliza ion due o any eason is
12%, including mo ali y (4.2%), unplanned su ‑
ge y (5.6%), and elapse o bac e emia (1.4%).
A isk di e ence (i.e., a non‑in e io i y ma ‑
gin) o 10 pe cen age poin s has been chosen.
Unde he assump ion o a 3% loss o ollow‑
up, we de e mined ha inclusion o 342 pa ien s
would be equi ed o p o ide a powe o 80%
and a le el o signi ica ion o 0.05 o con i m
non‑in e io i y.
The e will be he ollowing analysis popula‑
ions o his s udy. Modi ied Full Analysis Se
(mFAS): all pa ien s who a e andomized in o
he s udy and who ha e ecei ed he in es i‑
ga ional medicinal p oduc will be included in
he mFAS popula ion. The Sa e y popula ion: he
sa e y popula ion will ha e he same de ini ion
as he mFAS subse and, hus, all sa e y analy‑
sis will be conduc ed on he mFAS popula ion.
Pe P o ocol Popula ion: pe p o ocol pa ien se s
will be de ined as hose pa ien s included in he
mFAS se wi hou majo p o ocol de ia ions
ha migh impac he s udy’s main assessmen s.
These de ia ions will be assessed du ing he da a
e iew p io o da abase lock. An in e im analy‑
sis is planned o be ca ied ou by an independ‑
en DSMB (Da a Sa e y Moni o ing Boa d) upon
comple ion o 25% o he es ima ed sample size
(85 pa ien s).
Moni o ing
Ad e se e en (AE): an AE is any un owa d
medical occu ence in a clinical s udy subjec
adminis e ed a medicinal (in es iga ional o
non‑in es iga ional) p oduc . An AE does no
necessa ily ha e a causal ela ionship wi h he
ea men . The de ini ions o se ious ad e se
e en (SAE) and ad e se eac ion (AR), and he
assessmen o i s in ensi y g ade as well as he
assessmen o causali y will be de ined, egis‑
e ed, documen ed, and epo ed acco ding o
usual Good Clinical P ac ice (GCP) p ocedu es.
Pha maco igilance ac i i ies will be delega ed by
he sponso o a pha maco igilance cen e .
E hics
The ial will be conduc ed acco ding o he
p inciples o he las Decla a ion o Helsinki
(acco ded by he 64 h Wo ld Medical Associa‑
ion Gene al Assembly in 2013), he GCP, and
cu en legisla ion. The in es iga o is espon‑
sible o gua an eeing ha he clinical ial is
ealized ollowing he di ec i es es ablished by
he In e na ional Con e ence on Ha moniza ion
abou GCP and local legisla ion.
The s udy was au ho ized by he Spanish
Medicines and Heal hca e P oduc s Regula o y
Agency (Agencia Española de Medicamen os y
P oduc os Sani a ios; AEMPS) and he Clinical
Resea ch E hics Commi ee. The ial p o ocol
ecei ed AEMPS app o al on Decembe 15 2021
and he esea ch e hics commi ee app o al
on Ma ch 8 2022. A subs an ial amendmen
ecei ed AEMPS app o al and Clinical Resea ch
E hics Commi ee app o al on Janua y 25 and
Feb ua y 14 2023, espec i ely.
The p incipal in es iga o o collabo a o a
each si e will p o ide he in o ma ion shee s
o he pa ien s, and will explain he s udy
and objec i es and cla i y any doub s. They
will ob ain w i en in o med consen om all
pa ien s, o hei legal ep esen a i es (LRs) i
hey lack capaci y, be o e en olmen . Pa ien s
(o hei LRs) a e ee o wi hd aw om he ial
651
In ec Dis The (2025) 14:643–655
a any ime and his will be explici ly s a ed on
he pa ien ’s in o ma ion shee s.
Pa ien pe sonal and clinical in o ma ion will
be managed acco ding o Eu opean Regula ion
2016/679 and Spanish legisla ion. Pa ien da a
will be anonymized, iden i ying e e y pa ien by
a code. Only he s udy doc o and collabo a o s
ha e access o clinical his o y. Consequen ly,
he pa ien ’s iden i y will no be e ealed o
any o he pe son, excep in cases o medi‑
cal eme gency o i equi ed o do so by law.
Access o pa ien in o ma ion will be es ic ed
o he s udy doc o and collabo a o s, he heal h
au ho i ies (AEMPS), he Clinical Resea ch E h‑
ics Commi ee, and pe sonnel au ho ized by he
sponso when hey need o check he da a and
p ocedu es used in he s udy, bu always main‑
aining he con iden iali y o he said in o ma‑
ion in acco dance wi h cu en legisla ion.
DISCUSSION
Acco ding o classic ecommenda ions o he
ea men o IE, p olonged pa en e al an imic o‑
bial he apy is s ill alid o mos pa ien s [3, 4].
Howe e , p olonged hospi al s ay p edisposes
pa ien s o nosocomial complica ions, is asso‑
cia ed wi h a dele e ious unc ional impac in
he ge ia ic popula ion, and, inally, i inc eases
cos s and limi s he a ailabili y o beds in e ‑
ia y cen e s.
Ou pa ien pa en e al an ibio ic he apy
has ne e been es ed in he se ing o a an‑
domized clinical ial. While, in ui i ely, he
e icacy should be equal o OPAT compa ed
o pa en e al he apy in an inpa ien se ing,
pa ien s ollowing OPAT he apy may be con‑
olled less equen ly ha hose hospi alized.
Ou aim is o demons a e he non‑in e io i y
o ou pa ien o al an ibio ic he apy in com‑
pa ison wi h ou pa ien pa en e al an ibi‑
o ic ea men . As seconda y objec i es, we
will compa e he quali y o li e o pa ien s
included in bo h a ms, he cos s o in e en‑
ions h ough a pha maco‑economic sub‑s udy,
and he complica ions ela ed o pa en e al
and o al adminis a ion o an ibio ics (such
as ca he e ‑ ela ed e en s o supe in ec ions,
e.g., Clos idioides di icile dia hea). Ou s udy
he e o e s a s om a plausible hypo hesis
and will ollow a igo ous me hodology ha
includes he ealiza ion o a mul icen e an‑
domized clinical ial, wi h he pa icipa ion
o se e al uni e si y hospi als dis ibu ed
h oughou he coun y. On he basis ou lined
abo e, we conside he O aPAT‑IE GAMES s udy
o be easible, sa e, and wi h po en ially el‑
e an implica ions o clinical p ac ice in he
he apeu ic app oach o in ec i e endoca di is.
Many physicians and pa ien s con inue o eel
mo e com o able ending an ibio ic ea men
o IE by an in a enous ou e a home [16],
bu he OPAT op ion un o una ely s ill has
weake e idence han he o al one. The O a‑
PAT‑IE GAMES ial will p o ide solid e idence
o posi ion his s a egy as equi alen .
Howe e , ou s udy has se e al limi a ions
ha mus be acknowledged. Fi s ly, he ial
will e alua e he s a egies o o al and pa ‑
en e al an ibio ic he apy, bu ail o ha e
enough powe o demons a e di e ences pe
subg oups (e.g., na i e al e‑IE, p os he ic
al e‑IE, speci ic mic oo ganisms) due o he
p esumed low numbe o hese sub‑g oups.
Un o una ely, he sample sizes equi ed o
a speci ic s udy o each speci ic mic oo gan‑
ism o indica ion would make he ial com‑
ple ely un easible. Ou s udy, howe e , aims
o compa e ea men s a egies a he han
he ea men app oach o speci ic g oups o
speci ic an ibio ic combina ions. Secondly, i
is ce ainly impossible o pa ien s who com‑
ple e o al ea men a home o be ollowed
up as closely as pa ien s who comple e OPAT
ea men (wi h daily nu sing isi s), and much
less closely as pa ien s who a e hospi alized.
This limi a ion is, howe e , common in o he
clinical ials compa ing o al e sus pa en e al
s a egies. I is wo h cla i ying, howe e , ha
he sugges ed elephone con ac is app op i‑
a ely close o ensu e pa ien sa e y, and ace‑
o‑ ace isi s will be added whene e neces‑
sa y. Thi dly, al hough he sample size is la ge
(n=342), he 20 pa icipa ing cen e s ha e a
high olume o endoca di is pe yea , and we
es ima e hey will be able o include enough
pa ien s in his ial. Mo eo e , cen e s wi h‑
ou OPAT p og ams a e no included in his