Rifampicin at High Dose for Difficult-to-Treat Tuberculosis (RIAlta) study

Prior treatment

• The subject used any drugs or substances known to be strong inhibitors or inducers of cytochrome P450 enzymes which are involved in the degradation pathways of rifampicin within the time windows specified in table 2.
• Treatment with any of the following: rifampicin, isoniazid, pyrazinamide, ethambutol, levofloxacin, or moxifloxacin within the last month for at least 14 days or current TB treatment for more than 7 days.
• The subject is enrolled in any other investigational trial that includes a drug intervention.
• Subjects with solid organ transplantation or bone marrow transplantation.
• Subjects with an active onco-hematological neoplasm requiring chemotherapy or immune therapy.
• Previous severe pulmonary disease, other than pulmonary DS-TB, according to local investigator.

Other illness

• Pre-existing epilepsy or psychiatric disorder according to local investigator.
• Ischemic heart disease OR severe arrhythmia within 6 months OR Atrial Fibrillation with oral anticoagulant therapy indication when transitioning to low-molecular weight heparin is not feasible.
• Subjects with known allergy or sensitivity to rifampicin, or any of the other components of DS-TB treatment.

Lab values

• Signs of significant liver disease: o Liver enzymes (AST or ALT) > 5x upper limit of normal o Total bilirubin > 3x upper limit of normal o Subjects with a Child-Pugh grade C cirrhosis or acute decompensation of their chronic liver disease at enrolment. o Any other grade 3-4 hepatobiliary alteration according to the CTCAE v5.

Age

• Barthel index <40 for subjects older than 60 years old.

Other

• Rifampicin resistance confirmation.
• Positive pregnancy test
• Breastfeeding women.

• Subjects with confirmed or probable pulmonary or extra pulmonary DS-TB.
• Informed consent provided.
• Positive smear, positive Xpert MTB/RIF test, positive M. tuberculosis culture (confirmed cases) OR histological study compatible with necrotizing granulomas OR a liquid biochemistry (pleural, pericardial, ascites or cerebrospinal fluid) suggestive of TB together with clinical symptoms resembling TB disease in the absence of any other possible cause (probable cases).
• Female participants of childbearing age must have a negative pregnancy test at baseline.
• Age ≥ 60 years old; or Age ≥ 18 years and any of the followings: Body mass index ≤ 18.5 Human Immunodeficiency Virus (HIV) infection. Diabetes Mellitus Hepatitis C virus (HCV) infection (positive HCV serology) Hepatitis B virus (HBV) infection (positive HBV surface antigen or anti-core antibodies) Daily alcohol intake ≥ 2 units of alcohol (1 unit of alcohol: 4% alcohol 250ml (ie beer); 4.5% alcohol 218ml (i.e. cider); 13% alcohol 76ml (i.e. wine); 40% alcohol 25ml (i.e. whisky)) Chronic liver disease of any other cause (metabolic, toxic, autoimmune) Central Nervous System TB involvement