68fb2b8ab60ab8ad155126f2c743e93e pharmaceutics-15-00009-v3.pdf dd252987d93f0cb5568a61f6d2438b327c4d31bf pharmaceutics-15-00009-v3.pdf 60c5c58fb75687396a3ff971a77dd7336232b4cd783411fda41c1ca905d1ce9b pharmaceutics-15-00009-v3.pdf Title: Safety of Rifampicin at High Dose for Difficult-to-Treat Tuberculosis: Protocol for RIAlta Phase 2b/c Trial Subject: 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 > 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 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.-3pt Keywords: tuberculosis; rifampicin; clinical trial; vulnerable population Author: Juan Espinosa-Pereiro, Samiksha Ghimire, Marieke G. G. Sturkenboom, Jan-Willem C. Alffenaar, Margarida Tavares, Sarita Aguirre, Arturo Battaglia, Gladys Molinas, Teresa Tórtola, Onno W. Akkerman, Adrian Sanchez-Montalva and Cecile Magis-Escurra Creator: LaTeX with hyperref Producer: pdfTeX-1.40.25 CreationDate: Wed Nov 6 11:36:03 2024 CET ModDate: Thu Nov 7 03:24:48 2024 CET Custom Metadata: no Metadata Stream: no Tagged: no UserProperties: no Suspects: no Form: none JavaScript: no Pages: 13 Encrypted: no Page size: 595.276 x 841.89 pts (A4) Page rot: 0 File size: 610369 bytes Optimized: no PDF version: 1.7 name type encoding emb sub uni object ID ------------------------------------ ----------------- ---------------- --- --- --- --------- SOZKOC+VnURWPalladioL-Bold Type 1 Custom yes yes yes 10 0 GKMCSV+URWPalladioL-Bold Type 1 Custom yes yes yes 16 0 AMFDQD+URWPalladioL-Roma Type 1 Custom yes yes yes 22 0 VBNDMI+URWPalladioL-Ital Type 1 Custom yes yes yes 27 0 MSSEIU+CMSY10 Type 1 Builtin yes yes yes 32 0 HSNIKI+VnURWPalladioL Type 1 Custom yes yes yes 37 0 IAFAOG+TimesNewRomanPS-BoldItalicMT Type 1C WinAnsi yes yes no 57 0 MIGMCG+PalatinoLinotype-Bold CID TrueType Identity-H yes yes yes 100 0 MIGMCH+PalatinoLinotype-Roman CID TrueType Identity-H yes yes yes 106 0 MIGMEH+PalatinoLinotype-Italic CID TrueType Identity-H yes yes yes 112 0 MIGMFH+PalatinoLinotype-Italic TrueType WinAnsi yes yes no 118 0 MIGMFI+PalatinoLinotype-Bold TrueType WinAnsi yes yes no 121 0 MIGMFJ+PalatinoLinotype-Roman TrueType WinAnsi yes yes no 124 0 Jhove (Rel. 1.28.0, 2023-05-18) Date: 2025-02-22 02:49:54 CET RepresentationInformation: pharmaceutics-15-00009-v3.pdf ReportingModule: PDF-hul, Rel. 1.12.4 (2023-03-16) LastModified: 2025-02-21 14:17:42 CET Size: 610369 Format: PDF Version: 1.7 Status: Well-Formed and valid SignatureMatches: PDF-hul MIMEtype: application/pdf PDFMetadata: Objects: 282 FreeObjects: 1 IncrementalUpdates: 0 DocumentCatalog: PageLayout: SinglePage PageMode: UseNone Outlines: Item: Title: Introduction Destination: section.1 Item: Title: Methods Destination: section.2 Children: Item: Title: Study Design Destination: subsection.2.1 Item: Title: Objectives and Endpoints Destination: subsection.2.2 Item: Title: Study Setting Destination: subsection.2.3 Item: Title: Study Population and Eligibility Destination: subsection.2.4 Item: Title: Recruitment Destination: subsection.2.5 Item: Title: Intervention Destination: subsection.2.6 Item: Title: Rifampicin Dosing Strategies Destination: subsection.2.7 Item: Title: Assessment of Study Outcomes, Analysis Groups, and Duration of Follow-Up Destination: subsection.2.8 Item: Title: Sample Size Assumptions and Justification Destination: subsection.2.9 Item: Title: Main Outcomes Analysis Destination: subsection.2.10 Item: Title: Secondary Objectives Destination: subsection.2.11 Children: Item: Title: Microbiological Evaluation Destination: subsubsection.2.11.1 Item: Title: Pharmacokinetics Destination: subsubsection.2.11.2 Item: Title: Pharmacogenetics Destination: subsubsection.2.11.3 Item: Title: Health Economics and Quality of Life Destination: subsubsection.2.11.4 Item: Title: Ethical Approvals Destination: subsection.2.12 Item: Title: Sharing of Trial Findings Destination: subsection.2.13 Item: Title: Participant and Public Engagement Destination: subsection.2.14 Item: Title: Strengths and Weaknesses of the Design Destination: subsection.2.15 Item: Title: Discussion Destination: section.3 Item: Title: Conclusions Destination: section.4 Item: Title: Trial Status Destination: section.5 Item: Title: References Destination: section.6 Info: Title: Safety of Rifampicin at High Dose for Difficult-to-Treat Tuberculosis: Protocol for RIAlta Phase 2b/c Trial Author: Juan Espinosa-Pereiro, Samiksha Ghimire, Marieke G. G. Sturkenboom, Jan-Willem C. Alffenaar, Margarida Tavares, Sarita Aguirre, Arturo Battaglia, Gladys Molinas, Teresa Tórtola, Onno W. Akkerman, Adrian Sanchez-Montalva and Cecile Magis-Escurra Subject: 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 > 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 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.-3pt Keywords: tuberculosis; rifampicin; clinical trial; vulnerable population Creator: LaTeX with hyperref Producer: pdfTeX-1.40.25 CreationDate: Wed Nov 06 11:36:03 CET 2024 ModDate: Thu Nov 07 03:24:48 CET 2024 ID: 0x018331359b3ebfaa9b4735082658465c, 0x018331359b3ebfaa9b4735082658465c Filters: FilterPipeline: FlateDecode Fonts: Type1: Font: BaseFont: GKMCSV+URWPalladioL-Bold FontSubset: true FirstChar: 2 LastChar: 150 FontDescriptor: FontName: GKMCSV+URWPalladioL-Bold Flags: Symbolic FontBBox: -152, -301, 1000, 935 FontFile: true EncodingDictionary: Differences: true ToUnicode: true Font: BaseFont: MSSEIU+CMSY10 FontSubset: true FirstChar: 0 LastChar: 21 FontDescriptor: FontName: MSSEIU+CMSY10 Flags: Symbolic FontBBox: -29, -960, 1116, 775 FontFile: true ToUnicode: true Font: BaseFont: HSNIKI+VnURWPalladioL FontSubset: true FirstChar: 161 LastChar: 226 FontDescriptor: FontName: HSNIKI+VnURWPalladioL Flags: Symbolic FontBBox: 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