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

Vol.:(0123456789) Infect Dis Ther (2025) 14:643–655 https://doi.org/10.1007/s40121-025-01110-9 STUDY PROTOCOL Oral vs. Outpatient Parenteral Antimicrobial Treatment forInfective Endocarditis: Study Protocol fortheSpanish OraPAT‑IE GAMES Trial GuillermoCuervo · MartaHernández‑Meneses· ArístidesdeAlarcón· RafaelLuque‑Marquez· MaríaM.Alonso‑Socas· AnaLópez‑Lirola· VíctorGonzález‑Ramallo· AneJ.Goikoetxea‑Agirre· DavidNicolás· MiguelA.Goenaga· EsperanzaMerino · FrancescEscrihuela‑Vidal· PilarMartín‑Dávila· BelénLoeches· LucíaBoix‑Palop· OriolGasch· MartaCamprecios· AliciaHernández‑Torres· LaraGarcía‑Álvarez· MarcosPajarón· MaríaAngelsRibas· RosaBlanes‑Hernández· InmaculadaLópez‑Montesinos· LuisE.López‑Cortés· BárbaraVidal· MarianaFernández‑Pittol· DoloresNavarro· AsunciónMoreno· CoralSala· JuanAmbrosioni· JoséM.Miró· OraPAT‑IE GAMES Investigators Received: October 30, 2024 / Accepted: January 23, 2025 / Published online: March 1, 2025 © The Author(s) 2025 ABSTRACT Introduction: The POET trial demonstrated that moving from intravenous to oral antibiotics in stable patients with left‑sided infective endo‑ carditis (IE) was noninferior to fully parenteral treatment. However, it did not compare outpa‑ tient strategies. Methods: The OraPAT‑IE GAMES trial is a non‑ inferiority, multicenter, randomized, open‑label study aimed to compare partial oral versus out‑ patient 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 even‑ tually be included. After a minimum of 10 days of parenteral treatment, stable patients Dr. José M. Miró is member of the Reial Academia de Medicina de Catalunya (RAMC), Barcelona, Spain. Prior Presentation: The OraPAT‑IE GAMES trial opened its first site of recruitment in April 2022. The first patient was enrolled in August 2022. Preliminary data on patient recruitment for this study were presented in poster format at the 17th International Society of Infectious Cardiovascular Diseases (ISCVID) Symposium held in June 16–18, 2024, in Malmö, Sweden; and as an oral presentation at the 13th Congress of the Sociedad Española de Infecciones Cardiovasculares (SEICAV) held in November 22–23, 2024 in Bilbao, Spain. The abstract presented at both conferences (with updated preliminary recruitment data) can be seen as Appendix C of the supplementary material. The recruitment period has been extended until the end of 2026. OraPAT‑IE GAMES Investigators are listed in acknowledgements section. Supplementary Information The online version contains supplementary material available at https:// doi. org/ 10. 1007/ s40121‑ 025‑ 01110‑9. G.Cuervo(*)· M.Hernández‑Meneses· A.Moreno· C.Sala· J.Ambrosioni(*)· J.M.Miró Infectious Diseases Department, Hospital Clinic‑IDIBAPS, University ofBarcelona, Villarroel 170, 08036Barcelona, Spain e‑mail: [email protected] J. Ambrosioni e‑mail: [email protected] M. Hernández‑Meneses e‑mail: [email protected] A. Moreno e‑mail: [email protected] C. Sala e‑mail: [email protected] 644 Infect Dis Ther (2025) 14:643–655 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 demon‑ strate the equivalent efficacy of the two out‑ patient 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 impor‑ tance to demonstrate the effectiveness and safety of outpatient management strategies that could reduce the duration of conventional hos‑ pitalizations with their potential complications and inherent costs. Trial Registration: EudraCT: 2020‑001024‑34. ClinicalTrials.gov identifier: NCT05398679. J. M. Miró e‑mail: [email protected] G.Cuervo· A.deAlarcón· P.Martín‑Dávila· I.López‑Montesinos· L.E.López‑Cortés· J.Ambrosioni· J.M.Miró CIBERINFEC, Instituto de Salud Carlos III, Madrid, Spain e‑mail: [email protected] P. Martín‑Dávila e‑mail: [email protected] I. López‑Montesinos e‑mail: [email protected] L. E. López‑Cortés e‑mail: [email protected] A.deAlarcón· R.Luque‑Marquez· D.Navarro Clinical Unit ofInfectious Diseases, Microbiology andParasitology (UCEIMP), Institute ofBiomedicine ofSeville (IBiS), Virgen del Rocío University Hospital/CSIC/University ofSeville, Seville, Spain e‑mail: [email protected] D. Navarro e‑mail: [email protected] M.M.Alonso‑Socas· A.López‑Lirola Hospital Universitario de Canarias, Tenerife, Spain e‑mail: [email protected] A. López‑Lirola e‑mail: [email protected] V.González‑Ramallo Hospital General Universitario Gregorio Marañón, Madrid, Spain e‑mail: [email protected] A.J.Goikoetxea‑Agirre Hospital Universitario de Cruces, Bilbao, Spain e‑mail: [email protected] D.Nicolás Internal Medicine‑Home Hospitalization Unit, Hospital Clinic‑IDIBAPS, University ofBarcelona, Barcelona, Spain e‑mail: [email protected] M.A.Goenaga Hospital Universitario Donosti, Instituto Investigación Biogipuzkoa, SanSebastián, Spain e‑mail: [email protected] E.Merino Unit ofInfectious Diseases, Alicante General University Hospital ‑ Alicante Institute ofHealth andBiomedical Research (ISABIAL), Alicante, Spain e‑mail: [email protected] E.Merino Clinical Medicine Department, Miguel Hernández University, Elche, Spain F.Escrihuela‑Vidal Hospital Universitario de Bellvitge, Barcelona, Spain e‑mail: [email protected] P.Martín‑Dávila Hospital Universitario Ramón y Cajal, Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid, Spain B.Loeches Hospital Universitario La Paz, Madrid, Spain e‑mail: [email protected] L.Boix‑Palop Hospital Mutua de Terrassa, Terrassa, Spain e‑mail: [email protected] O.Gasch Servei de Malalties Infeccioses, Hospital Universitari Parc Taulí, Institut d’Investigació i Innovació Parc Taulí (I3PT‑CERCA), Universitat Autònoma de Barcelona, Sabadell, Spain e‑mail: [email protected] M.Camprecios Hospital de la Santa Creu y Sant Pau, Barcelona, Spain e‑mail: [email protected] 645 Infect Dis Ther (2025) 14:643–655 Keywords: Randomized controlled trial; Infective endocarditis; Mortality; Oral antibiotic therapy; Oral step‑down antibiotic treatment; Partial oral treatment; OPAT; Outpatient parenteral antibiotic treatment; Reinfections; Relapses Key Summary Points The OraPAT‑IE GAMES is the first randomized clinical trial to compare the two outpatient strategies available for patients with stable infective endocarditis in the consolidation phase of antibiotic treatment. Although the planned sample size is large (n=342), it will be carried out in 20 hospitals within the multicenter and multidiscipli‑ nary GAMES study group, so it is considered feasible. This study will presumably share the inher‑ ent limitations of its open label design. Fur‑ thermore, the trial will evaluate oral versus parenteral antibiotic therapy strategies but will not be powered to demonstrate differ‑ ences between various subgroups of IE (e.g., native valve IE, prosthetic valve IE, specific micro‑organisms, etc.). Beyond the aforementioned limitations, this study could have a relevant impact on clini‑ cal practice, improving the quality of life of patients and allowing the shortening of con‑ ventional hospitalizations with their inherent complications and costs. INTRODUCTION Although infective endocarditis (IE) is a rare infectious disease, with crude annual inci‑ dence rates ranging between 1.5 and 9.0 cases per 100,000 people, mortality has remained relatively stable at around 20% during hospi‑ talization, and more than 30% per year [1]. In Spain, the crude annual incidence is estimated at around 3 cases per 100,000 people, showing a slight but constant increase [2]. This incidence represents approximately 1600 new cases of IE per year in our country. Some classic recommendations for the treat‑ ment of IE have remained stable and valid for decades. These include: (1) the need for pro‑ longed antimicrobial therapy (4–6 weeks); (2) A.Hernández‑Torres Hospital Virgen de la Arrixaca, Murcia, Spain e‑mail: [email protected] L.García‑Álvarez Hospital San Pedro‑CIBIR, Logroño, Spain e‑mail: [email protected] M.Pajarón Hospital Marqués de Valdecilla, Santander, Spain e‑mail: [email protected] M.A.Ribas Hospital Son Espases, Palma, Spain e‑mail: [email protected] R.Blanes‑Hernández Hospital de La Fe, Valencia, Spain e‑mail: [email protected] I.López‑Montesinos Hospital del Mar, Barcelona, Spain L.E.López‑Cortés Unidad Clínica de Enfermedades Infecciosas y Microbiología, Hospital Universitario Virgen Macarena, Seville, Spain L.E.López‑Cortés Departamentos de Medicina y Microbiología, Facultad de Medicina, Universidad de Sevilla, Seville, Spain L.E.López‑Cortés Instituto de Biomedicina de Sevilla (IBiS)/CSIC, Seville, Spain B.Vidal Cardiology Department, Hospital Clinic‑IDIBAPS, University ofBarcelona, Barcelona, Spain e‑mail: [email protected] M.Fernández‑Pittol Microbiology Department, Hospital Clinic‑IDIBAPS, University ofBarcelona, Barcelona, Spain e‑mail: [email protected] 646 Infect Dis Ther (2025) 14:643–655 parenteral administration; (3) with bactericidal antimicrobials; and (4) in hospitalized patients, given the high complexity of its management. In fact, all these recommendations are still valid in the most recent American and Euro‑ pean guidelines [3, 4]. However, the need for a prolonged hospital stay predisposes patients to nosocomial complications, such as colonization with resistant microbiological flora and noso‑ comial infections, and, furthermore, its associa‑ tion with a marked deterioration in functional status has been observed in geriatric patients [5]. Additionally, this increases costs and limits the availability of beds for patients in tertiary centers. Outpatient parenteral antibiotic therapy (OPAT) has been shown to be effective and safe for the treatment of infective endocarditis (IE) in selected cases [6–11]. However, until recently, most infectious disease guidelines had restrictive criteria for OPAT for this disease. In a work pub‑ lished by the GAMES group (Grupo de Apoyo al Manejo de la Endocarditis en España), it was concluded that these recommendations could be greatly expanded [12]. On the other hand, a parenteral route can be a source of serious complications (e.g., throm‑ bosis or bacteremia). Additionally, intravenous antibiotics are generally expensive. Oral antibi‑ otic therapy could reduce these complications and be an appropriate alternative, but experi‑ ence with left‑sided endocarditis was limited to small series and cohort studies [13]. The large POET randomized clinical trial published in 2019 demonstrated that a significant propor‑ tion of patients with left‑sided IE could benefit from oral antibiotic therapy, with efficacy and safety comparable to parenteral treatment [14]. In this trial, however, all patients in the paren‑ teral arm and most of those included in the oral arm, completed their treatment regimens in con‑ ventional hospitalization. To date, no trial has compared the efficacy and safety of OPAT versus outpatient oral therapy for this group of well‑ selected patients. The OraPAT‑IE GAMES trial (ClinicalTrials. gov ID: NCT05398679), currently recruiting, may provide the necessary evidence to choose one modality over another and to identify spe‑ cific groups that may benefit more from one of these strategies. We aimed to demonstrate the non‑inferiority of oral outpatient antibiotic therapy in comparison with OPAT. As second‑ ary objectives, we will compare the quality of life of patients included in both arms, the costs of interventions through a pharmaco‑economic sub‑study, and the complications related to par‑ enteral and oral administration of antibiotics (such as antibiotics or catheter‑related adverse events and superinfections, e.g., Clostridioides difficile diarrhea). METHODS Study Design The OraPAT‑IE GAMES study is a nationwide, noninferiority, multicenter, prospective, rand‑ omized, controlled, open, non‑inferiority (delta 10%) clinical trial. Randomization will be done 1:1 and will be performed online through a cen‑ tralized computer system. Eligible Patients Patients included in the study must meet all the following inclusion criteria: (1) left‑sided native or prosthetic definite infective endocarditis based on the modified Duke criteria infected with one of the following non‑resistant micro‑ organisms: non‑resistant streptococci and other Gram positive cocci, e.g., Granulicatella and Abiotrophia, Enterococcus faecalis, Staphylococcus aureus, coagulase‑negative staphylococci, and HACEK group (Haemophilus spp., Aggregatibacter spp., Cardiobacterium hominis, Eikenella corrodens, and Kingella spp); (2)≥18 years old; (3)≥10 days of appropriate parenteral antibi‑ otic treatment overall and at least 1week of appropriate parenteral treatment after valve surgery (a positive valve culture change the overall duration of treatment, but not affecting the patient’s eligibility); (4) T<38.0°C for more than 2days; (5) C‑reactive protein that dropped below 25% of the peak value or below an abso‑ lute value of 20mg/L, and the white blood cell count dropped to less than 15× 109/L during antibiotic treatment; (6) no sign of abscess for‑ mation revealed by echocardiography; and (7) 647 Infect Dis Ther (2025) 14:643–655 transthoracic (TTE) and/or transoesophageal echocardiography (TEE) performed preferably within 48 h of randomization (TEE is not man‑ datory if TTE is of good and reassuring quality). Echoscopy (portable echocardiograms) are also admitted, as long as they are registered on the clinical history. Exclusion Criteria (1) Body mass index>40; (2) concomitant infec‑ tion requiring intravenous antibiotic therapy; (3) inability to give informed consent to par‑ ticipation; (4) suspicion of reduced absorption of oral treatment due to abdominal disorder; (5) micro‑organisms other than those defined in inclusion criteria; (6) any immunosuppres‑ sive disease or any medical condition at the discretion of the investigator that may preclude oral or OPAT therapy; (7) no family or appropri‑ ate home support; (8) reduced compliance; (9) women of childbearing potential with a positive pregnancy test, or participants (male or female) who wish to plan a pregnancy during the trial period; and (10) women in lactancy period. Setting The study is being carried out in 20 Spanish uni‑ versity hospitals, coordinated by the Hospital Clinic de Barcelona: Hospital de Sant Pau I la Santa Creu, Barcelona; Hospital Universitario de Bellvitge, Barcelona; Hospital Virgen del Rocío, Sevilla; Hospital Virgen Macarena, Sevilla; Hos‑ pital Gregorio Marañón, Madrid; Hospital de Cruces, Bilbao; Hospital de Donostia, Guipuz‑ koa; Hospital San Pedro, Logroño; Hospital Marqués de Valdecilla, Santander; Hospital Uni‑ versitario de Canarias, Tenerife; Hospital Son Espases, Palma Mallorca; Consorci Sanitari Parc Taulí de Sabadell, Barcelona; Hospital General Universitario de Alicante, Alicante; Hospital Universitario La Paz, Madrid; Hospital Clínico Universitario Virgen de la Arrixaca, Murcia; Hos‑ pital Universitario y Politécnico La Fe, Valencia; Hospital Universitari Mútua Terrassa, Terrassa, Barcelona; Hospital Universitario Ramón y Cajal, Madrid; and Hospital del Mar, Barcelona. Intervention The initial parental IE treatment will be in accordance with the European guidelines [8]. Selected patients (n=342) with left‑side IE and specific microorganisms (Staphylococcus aureus, coagulase negative staphylococci, Streptococcus spp., Enterococcus spp., and other selected micro‑ organisms), and available oral options will be randomized 1:1 to finish antibiotic therapy on either outpatient parenteral or oral regimens (with two active oral drugs; see Appendix A in the supplementary material). Before randomi‑ zation, patients will have completed at least 10days of intravenous therapy, and/or after 7days in the case of cardiac valvular surgery for IE, and have shown good clinical evolution and no clinical or echocardiographic signs of poten‑ tial bad prognosis. After randomization, the patient must follow the assigned treatment (oral vs. OPAT) for at least 25% of the total duration of treatment for their endocarditis. Parenteral con‑ solidation treatment in the OPAT regimen arm will be selected at the discretion of the treating physician and following the recommendations of current clinical guidelines. It may consist of conventional antibiotics for daily administra‑ tion as well as “long‑acting” options [4]. Primary Endpoint The composite endpoint (whatever happen first) consists of unplanned hospitalization due to any reason, all‑cause mortality, unplanned cardiac surgery and IE relapse of positive blood cultures with the primary pathogen within 6months from diagnosis. Unplanned cardiac surgery is defined as surgery of the heart not planned before randomization. Surgery due to sterile pericardial effusion or hemorrhage is, however, not included in this endpoint. Secondary end‑ points are patient satisfaction (standardized questionnaires), complications related to par‑ enteral administration and oral administration of antibiotics,e.g., antibiotic adverse reactions, 648 Infect Dis Ther (2025) 14:643–655 catheter‑related adverse events, e.g., phlebitis and line‑related bloodstream infections, and superinfections, e.g., Clostridioides difficile diar‑ rhea. Finally, also as a secondary objective of this trial, a cost–efficacy analysis will be conducted to compare healthcare costs in both study arms. Only direct costs will be included and the costs will be estimated from the National health Sys‑ tem perspective. The costs that we will include are: staff, pharmacy (drugs and consumables), transportation of staff to patients’ homes, diag‑ nostic tests, structural costs, cost of adverse events and catheter complications, emergency room visits, and hospital readmissions [15]. Follow‑Up Patients will be followed up for 6 months after the cessation of antibiotic treatment. Follow‑up examinations at 1 and 6 months will include clinical examinations and measurement of white blood cell count, C‑reactive protein, and blood cultures (Fig.1; and trial schedule in Table1). The follow‑up design is aimed to be as similar as possible to normal clinical practice, requesting essential examinations and leaving it up to the treating physicians to request additional studies according to each specific case. Follow‑up TTE will also be requested according to the criteria of the treating physicians. Statistical Analysis Plan The statistical analysis will be carried out in accordance with the principles specified in the International Conference on Harmonization (ICH) Topic E9 (CPMP/ICH/363/96). A detailed Statistical Analysis Plan (SAP) agreed upon by the Sponsor and the Project Statistician will be available before the database closure. This SAP will follow the general regulatory recom‑ mendations given in the ICHE9 guidance, as well as other specific guidance on methodolog‑ ical and statistical issues. Also, it will stick to Fig. 1 Study design. EOT end of treatment, IE infective endocarditis, IV intravenous, m1 first month of follow-up, m3 third month of follow-up, OPAT outpatient parenteral antibiotic treatment, TOC test of cure 649 Infect Dis Ther (2025) 14:643–655 Table 1 The OraPAT-IE GAMES visit schedule and study procedures Biochemistry will include at least glycemia, ionogram, CRP, and creatinine, and all other determinations at the discretion of the investigator. Hematology will include hematocrit, WBC count with differential count and platelets, and all other determinations at the discretion of the investigator a Will be taken at baseline and repeated when clinically indicated until end of treatment (EOT). Other cultures (urine, sputum, etc.) may be considered at the discretion of the investigator b Regular visits are periodical visits, the visit periodicity being defined as for patients with parenteral treatment, as daily visits or every 48h, with one entry per week recorded in the eCRD. Each center can organize visits according to its usual practice, but at least one telephone control and one weekly face-to-face visit is suggested (the latter must be registered in the eCRD), until the end of the study treatment c When clinically indicated by the investigator team, at least once weekly Screen period Baseline Nurse regular visitsb EOT Month 1 Month 3 Month 6 Early termination Eligibility, consent signature Parenteral antimicrobials according to inclusion criteria x Randomization x Full exam x History, exam and safety evaluation xxxxxxx Demographic data x Blood culturesa x x x x x Hematology x xcxxxxx Biochemistry x xcxxxxx Pregnancy test x x x Volume of blood (mL) 20mL Up to 20mL Up to 20mL Up to 20mL Up to 20mL Up to 20mL Up to 20mL Total volume of blood (mL) 650 Infect Dis Ther (2025) 14:643–655 the recommendations given by the consensus documents of the scientific journals to improve the reliability and value of medical research lit‑ erature by promoting transparent and accurate reporting of clinical research studies. The SAS System (Release 9.4, or an upgraded version), or equivalent validated statistical soft‑ ware, will be the statistical software used to analyze the datasets. A summary of the overall approach to statistical analysis is presented here‑ after. The trial is designed as a non‑inferiority trial, and hence to determine whether partial oral treatment is non‑inferior to OPAT. Accord‑ ing to our own rates for the primary endpoint, unplanned hospitalization due to any reason is 12%, including mortality (4.2%), unplanned sur‑ gery (5.6%), and relapse of bacteremia (1.4%). A risk difference (i.e., a non‑inferiority mar‑ gin) of 10 percentage points has been chosen. Under the assumption of a 3% loss to follow‑ up, we determined that inclusion of 342 patients would be required to provide a power of 80% and a level of signification of 0.05 to confirm non‑inferiority. There will be the following analysis popula‑ tions for this study. Modified Full Analysis Set (mFAS): all patients who are randomized into the study and who have received the investi‑ gational medicinal product will be included in the mFAS population. The Safety population: the safety population will have the same definition as the mFAS subset and, thus, all safety analy‑ sis will be conducted on the mFAS population. Per Protocol Population: per protocol patient sets will be defined as those patients included in the mFAS set without major protocol deviations that might impact the study’s main assessments. These deviations will be assessed during the data review prior to database lock. An interim analy‑ sis is planned to be carried out by an independ‑ ent DSMB (Data Safety Monitoring Board) upon completion of 25% of the estimated sample size (85 patients). Monitoring Adverse event (AE): an AE is any untoward medical occurrence in a clinical study subject administered a medicinal (investigational or non‑investigational) product. An AE does not necessarily have a causal relationship with the treatment. The definitions of serious adverse event (SAE) and adverse reaction (AR), and the assessment of its intensity grade as well as the assessment of causality will be defined, regis‑ tered, documented, and reported according to usual Good Clinical Practice (GCP) procedures. Pharmacovigilance activities will be delegated by the sponsor to a pharmacovigilance center. Ethics The trial will be conducted according to the principles of the last Declaration of Helsinki (accorded by the 64th World Medical Associa‑ tion General Assembly in 2013), the GCP, and current legislation. The investigator is respon‑ sible for guaranteeing that the clinical trial is realized following the directives established by the International Conference on Harmonization about GCP and local legislation. The study was authorized by the Spanish Medicines and Healthcare Products Regulatory Agency (Agencia Española de Medicamentos y Productos Sanitarios; AEMPS) and the Clinical Research Ethics Committee. The trial protocol received AEMPS approval on December 15 2021 and the research ethics committee approval on March 8 2022. A substantial amendment received AEMPS approval and Clinical Research Ethics Committee approval on January 25 and February 14 2023, respectively. The principal investigator or collaborator at each site will provide the information sheets to the patients, and will explain the study and objectives and clarify any doubts. They will obtain written informed consent from all patients, or their legal representatives (LRs) if they lack capacity, before enrolment. Patients (or their LRs) are free to withdraw from the trial 651 Infect Dis Ther (2025) 14:643–655 at any time and this will be explicitly stated on the patient’s information sheets. Patient personal and clinical information will be managed according to European Regulation 2016/679 and Spanish legislation. Patient data will be anonymized, identifying every patient by a code. Only the study doctor and collaborators have access to clinical history. Consequently, the patient’s identity will not be revealed to any other person, except in cases of medi‑ cal emergency or if required to do so by law. Access to patient information will be restricted to the study doctor and collaborators, the health authorities (AEMPS), the Clinical Research Eth‑ ics Committee, and personnel authorized by the sponsor when they need to check the data and procedures used in the study, but always main‑ taining the confidentiality of the said informa‑ tion in accordance with current legislation. DISCUSSION According to classic recommendations for the treatment of IE, prolonged parenteral antimicro‑ bial therapy is still valid for most patients [3, 4]. However, prolonged hospital stay predisposes patients to nosocomial complications, is asso‑ ciated with a deleterious functional impact in the geriatric population, and, finally, it increases costs and limits the availability of beds in ter‑ tiary centers. Outpatient parenteral antibiotic therapy has never been tested in the setting of a ran‑ domized clinical trial. While, intuitively, the efficacy should be equal for OPAT compared to parenteral therapy in an inpatient setting, patients following OPAT therapy may be con‑ trolled less frequently that those hospitalized. Our aim is to demonstrate the non‑inferiority of outpatient oral antibiotic therapy in com‑ parison with outpatient parenteral antibi‑ otic treatment. As secondary objectives, we will compare the quality of life of patients included in both arms, the costs of interven‑ tions through a pharmaco‑economic sub‑study, and the complications related to parenteral and oral administration of antibiotics (such as catheter‑related events or superinfections, e.g., Clostridioides difficile diarrhea). Our study therefore starts from a plausible hypothesis and will follow a rigorous methodology that includes the realization of a multicenter ran‑ domized clinical trial, with the participation of several university hospitals distributed throughout the country. On the basis outlined above, we consider the OraPAT‑IE GAMES study to be feasible, safe, and with potentially rel‑ evant implications for clinical practice in the therapeutic approach to infective endocarditis. Many physicians and patients continue to feel more comfortable ending antibiotic treatment for IE by an intravenous route at home [16], but the OPAT option unfortunately still has weaker evidence than the oral one. The Ora‑ PAT‑IE GAMES trial will provide solid evidence to position this strategy as equivalent. However, our study has several limitations that must be acknowledged. Firstly, the trial will evaluate the strategies of oral and par‑ enteral antibiotic therapy, but fail to have enough power to demonstrate differences per subgroups (e.g., native valve‑IE, prosthetic valve‑IE, specific microorganisms) due to the presumed low number for these sub‑groups. Unfortunately, the sample sizes required for a specific study for each specific microorgan‑ ism or indication would make the trial com‑ pletely unfeasible. Our study, however, aims to compare treatment strategies rather than the treatment approach for specific groups or specific antibiotic combinations. Secondly, it is certainly impossible for patients who com‑ plete oral treatment at home to be followed up as closely as patients who complete OPAT treatment (with daily nursing visits), and much less closely as patients who are hospitalized. This limitation is, however, common in other clinical trials comparing oral versus parenteral strategies. It is worth clarifying, however, that the suggested telephone contact is appropri‑ ately close to ensure patient safety, and face‑ to‑face visits will be added whenever neces‑ sary. Thirdly, although the sample size is large (n=342), the 20 participating centers have a high volume of endocarditis per year, and we estimate they will be able to include enough patients in this trial. Moreover, centers with‑ out OPAT programs are not included in this