{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,24]],"date-time":"2026-01-24T16:34:42Z","timestamp":1769272482112,"version":"3.49.0"},"reference-count":34,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2022,12,20]],"date-time":"2022-12-20T00:00:00Z","timestamp":1671494400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000780","name":"European Union\u2019s Horizon 2020","doi-asserted-by":"publisher","award":["823890"],"award-info":[{"award-number":["823890"]}],"id":[{"id":"10.13039\/501100000780","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceutics"],"abstract":"<jats:p>Previous clinical trials for drug-susceptible tuberculosis (DS-TB) have shown that first-line treatment with doses of rifampicin up to 40 mg\/kg are safe and increase the early treatment response for young adults with pulmonary tuberculosis. This may lead to a shorter treatment duration for those persons with TB and a good baseline prognosis, or increased treatment success for vulnerable subgroups (age &gt; 60, diabetes, malnutrition, HIV, hepatitis B or hepatitis C coinfection, TB meningitis, stable chronic liver diseases). Here, we describe the design of a phase 2b\/c clinical study under the hypothesis that rifampicin at 35 mg\/kg is as safe for these vulnerable groups as for the participants included in previous clinical trials. RIAlta is an interventional, open-label, multicenter, prospective clinical study with matched historical controls comparing the standard DS-TB treatment (isoniazid, pyrazinamide, and ethambutol) with rifampicin at 35 mg\/kg (HR35ZE group) vs. rifampicin at 10 mg\/kg (historical HR10ZE group). The primary outcome is the incidence of grade \u2265 3 Adverse Events or Severe Adverse Events. A total of 134 participants will be prospectively included, and compared with historical matched controls with at least a 1:1 proportion. This will provide a power of 80% to detect non-inferiority with a margin of 8%. This study will provide important information for subgroups of patients that are more vulnerable to TB bad outcomes and\/or treatment toxicity. Despite limitations such as non-randomized design and the use of historical controls, the results of this trial may inform the design of future more inclusive clinical trials, and improve the management of tuberculosis in subgroups of patients for whom scientific evidence is still scarce. Trial registration: EudraCT 2020-003146-36, NCT04768231.<\/jats:p>","DOI":"10.3390\/pharmaceutics15010009","type":"journal-article","created":{"date-parts":[[2022,12,21]],"date-time":"2022-12-21T03:31:06Z","timestamp":1671593466000},"page":"9","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Safety of Rifampicin at High Dose for Difficult-to-Treat Tuberculosis: Protocol for RIAlta Phase 2b\/c Trial"],"prefix":"10.3390","volume":"15","author":[{"given":"Juan","family":"Espinosa-Pereiro","sequence":"first","affiliation":[{"name":"International Health Unit Vall d\u2019Hebron-Drassanes, Infectious Diseases Department, Vall d\u2019Hebron University Hospital, Department of Medicine Universitat Aut\u00f3noma de Barcelona, Programa de Salut Internacional del Institut Catal\u00e1 de Salut (PROSICS), 08035 Barcelona, Spain"},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Enfermedades Infecciosas (CIBERINFEC), Instituto de Salud Carlos III, 28029 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Samiksha","family":"Ghimire","sequence":"additional","affiliation":[{"name":"Department Clinical Pharmacy and Pharmacology, University Medical Center Groningen, University of Groningen, 9700 RB Groningen, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3420-0591","authenticated-orcid":false,"given":"Marieke","family":"Sturkenboom","sequence":"additional","affiliation":[{"name":"Department Clinical Pharmacy and Pharmacology, University Medical Center Groningen, University of Groningen, 9700 RB Groningen, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6703-0288","authenticated-orcid":false,"given":"Jan-Willem","family":"Alffenaar","sequence":"additional","affiliation":[{"name":"Department Clinical Pharmacy and Pharmacology, University Medical Center Groningen, University of Groningen, 9700 RB Groningen, The Netherlands"},{"name":"School of Pharmacy, Faculty of Medicine and Health, The University of Sydney, Sydney, NSW 2006, Australia"},{"name":"Westmead Hospital, Sydney, NSW 2145, Australia"},{"name":"Sydney Institute for Infectious Diseases, The University of Sydney, Sydney, NSW 2006, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4518-2197","authenticated-orcid":false,"given":"Margarida","family":"Tavares","sequence":"additional","affiliation":[{"name":"Infectious Diseases Service, Centro Hospitalar de S\u00e3o Jo\u00e3o, 4200-319 Porto, Portugal"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sarita","family":"Aguirre","sequence":"additional","affiliation":[{"name":"National Program for Tuberculosis, Ministry of Health, Asunci\u00f3n 1430, Paraguay"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Arturo","family":"Battaglia","sequence":"additional","affiliation":[{"name":"Instituto Nacional de Enfermedades Respiratorias y Ambientales, Asunci\u00f3n 1430, Paraguay"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gladys","family":"Molinas","sequence":"additional","affiliation":[{"name":"Instituto Nacional de Enfermedades Respiratorias y Ambientales, Asunci\u00f3n 1430, Paraguay"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Teresa","family":"T\u00f3rtola","sequence":"additional","affiliation":[{"name":"Microbiology Department, Vall d\u2019Hebron University Hospital, 08035 Barcelona, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Onno","family":"Akkerman","sequence":"additional","affiliation":[{"name":"TB Center Beatrixoord, Haren, University Medical Center Groningen, University of Groningen, 9751 ND Groningen, The Netherlands"},{"name":"Department of Pulmonary Diseases and Tuberculosis, University Medical Center Groningen, University of Groningen, 9700 RB Groningen, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Adrian","family":"Sanchez-Montalva","sequence":"additional","affiliation":[{"name":"International Health Unit Vall d\u2019Hebron-Drassanes, Infectious Diseases Department, Vall d\u2019Hebron University Hospital, Department of Medicine Universitat Aut\u00f3noma de Barcelona, Programa de Salut Internacional del Institut Catal\u00e1 de Salut (PROSICS), 08035 Barcelona, Spain"},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Enfermedades Infecciosas (CIBERINFEC), Instituto de Salud Carlos III, 28029 Madrid, Spain"},{"name":"Grupo de Estudio de Infecciones por Micobacterias, Sociedad Espa\u00f1ola de Enfermedades Infecciosas y Microbiolog\u00eda Cl\u00ednica (GEIM-SEIMC), 28003 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8424-9425","authenticated-orcid":false,"given":"Cecile","family":"Magis-Escurra","sequence":"additional","affiliation":[{"name":"Radboud University Medical Centre, Department of Respiratory Diseases-TB Expert Center Dekkerswald, 6561 KE Nijmegen, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,12,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1705","DOI":"10.1056\/NEJMoa2033400","article-title":"Four-Month Rifapentine Regimens with or without Moxifloxacin for Tuberculosis","volume":"384","author":"Dorman","year":"2021","journal-title":"N. 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