Oral vs. outpatient parenteral antimicrobial treatment for infective endocarditis: study protocol for the spanish oralPAT‑IE GAMES Trial
Abstract
Introduction The POET trial demonstrated that moving from intravenous to oral antibiotics in stable patients with left-sided infective endocarditis (IE) was noninferior to fully parenteral treatment. However, it did not compare outpatient strategies. Methods The OraPAT-IE GAMES trial is a noninferiority, multicenter, randomized, open-label study aimed to compare partial oral versus outpatient parenteral antibiotic therapy (OPAT) for consolidation of antibiotic treatment in left-sided IE. A total of 342 stable patients with IE caused by selected micro-organisms will eventually be included. After a minimum of 10 days of parenteral treatment, stable patients are randomized to oral therapy or OPAT. The primary end-point is a composite of all-cause mortality, unplanned cardiac surgery, relapse of positive blood cultures and/or unplanned hospital admission. Patients are followed-up for 6 months after completing antibiotic therapy. Planned Outcome This trial seeks to demonstrate the equivalent efficacy of the two outpatient strategies currently available for stable patients with IE in the consolidation phase of antibiotic treatment. Conclusion In a global context of limited healthcare resources and a sustained increase in elderly and frail patients, it is of great importance to demonstrate the effectiveness and safety of outpatient management strategies that could reduce the duration of conventional hospitalizations with their potential complications and inherent costs.
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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 heSpanish O aPAT‑IE GAMES T ial
Guille moCue o · Ma aHe nández‑Meneses· A ís idesdeAla cón· Ra aelLuque‑Ma quez·
Ma íaM.Alonso‑Socas· AnaLópez‑Li ola· Víc o González‑Ramallo· AneJ.Goikoe xea‑Agi e· Da idNicolás·
MiguelA.Goenaga· Espe anzaMe ino · F ancescEsc ihuela‑Vidal· Pila Ma ín‑Dá ila· BelénLoeches·
LucíaBoix‑Palop· O iolGasch· Ma aCamp ecios· AliciaHe nández‑To es· La aGa cía‑Ál a ez·
Ma cosPaja ón· Ma íaAngelsRibas· RosaBlanes‑He nández· InmaculadaLópez‑Mon esinos·
LuisE.López‑Co és· Bá ba aVidal· Ma ianaFe nández‑Pi ol· Dolo esNa a o· AsunciónMo eno·
Co alSala· JuanAmb osioni· JoséM.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, 08036Ba 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]
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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
6mon 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.deAla 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.deAla cón· R.Luque‑Ma quez· D.Na a o
Clinical Uni o In ec ious Diseases, Mic obiology
andPa 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, SanSebas 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
andBiomedical 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]
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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 1week 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 2days; (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 20mg/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
10days o in a enous he apy, and/o a e
7days 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 6mon 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 Table1).
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 48h, 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)
20mL Up o 20mL Up o
20mL
Up o
20mL
Up o
20mL
Up o
20mL
Up o
20mL
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