E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated | Pulmonary and extrapulmonary tuberculosis | |
E.1.1.1 | Medical condition in easily understood language | Pulmonary and extrapulmonary tuberculosis | |
E.1.1.2 | Therapeutic area | Diseases [C] - Bacterial Infections and Mycoses [C01] |
MedDRA Classification |
E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial | To evaluate the safety of high-dose rifampicin (35 mg/kg/d) supplemented with standard doses of isoniazid, pyrazinamide, and ethambutol for 8 weeks in adult subjects with pulmonary or extrapulmonary drug susceptible tuberculosis (DS-TB) belonging to difficult to treat subgroups. | |
E.2.2 | Secondary objectives of the trial | To evaluate the tolerability (of high-dose rifampicin (35 mg/kg/d) supplemented with standard doses of isoniazid, pyrazinamide, and ethambutol for 8 weeks in adult subjects with pulmonary or extrapulmonary TB belonging to difficult to treat patient subgroups. To evaluate the efficacy of high dose rifampicin (35 mg/kg) supplemented with standard doses of isoniazid, pyrazinamide, and ethambutol for 8 weeks by assessing early sterilizing activity in the sputum of pulmonary TB subjects belonging to difficult to treat patient subgroups. | |
E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives | 1-To describe pharmacokinetics-pharmacodynamics (PK/PD) of rifampicin at high doses in difficult-to-treat pulmonary and extrapulmonary TB. 2-To describe tuberculosis associated costs and the quality of life of DSTB participants. | |
E.3 | Principal inclusion criteria | The participant must fulfill either criteria nr. 1-4 AND nr. 5 OR criteria nr. 1-4 AND 6, AND anyone of 7-14: 1. Subjects with confirmed or probable pulmonary or extra pulmonary DS-TB. 2. Informed consent provided. 3. 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). 4. Female participants of childbearing age must have a negative pregnancy test at baseline. AND 5. Age ≥ 60 years old. OR 6. Age ≥ 18 years AND one of the following 7. Body mass index ≤ 18.5 8. Human Immunodeficiency Virus (HIV) infection. 9. Diabetes Mellitus 10. Hepatitis C virus (HCV) infection (positive HCV serology) 11. Hepatitis B virus (HBV) infection (positive HBV surface antigen) 12. 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)) 13. Chronic liver disease of any other cause (metabolic, toxic, autoimmune) 14. Central Nervous System TB involvement | |
E.4 | Principal exclusion criteria | Subjects will be excluded from entry if ANY ONE of the criteria listed below is met: 1. Rifampicin resistance confirmation. 2. Barthel index <40 for subjects older than 60 years old. 3. Signs of liver disease not related to TB [Liver enzymes (AST or ALT) > 5x upper limit of normal , Total bilirubin > 5x upper limit of normal, Patients with a Child-Pugh grade C cirrhosis or acute decompensation of their chronic liver disease at enrolment.] 4. Subjects with known allergy or sensitivity to rifampicin, or any of the other components of DS-TB treatment. 5. 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. 6. The subject is enrolled in any other investigational trial that includes a drug intervention. 7. Subjects with solid organ transplantation or bone marrow transplantation. 8. Subjects with an active onco-hematological neoplasm. 9. Previous severe pulmonary disease, other than pulmonary DS-TB, according to local investigator. 10. Pre-existing epilepsy or psychiatric disorder according to local investigator. 11. 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. 12. Positive pregnancy test 13. Breastfeeding women. 14. 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 the protocol. | |
E.5 End points |
E.5.1 | Primary end point(s) | Proportion of participants experiencing severe adverse events (grade 3 or superior according to the Common Terminology Criteria for Adverse Events, CTCAE version 5) compared to historical controls on 10mg/kg/day of rifampicin. | |
E.5.1.1 | Timepoint(s) of evaluation of this end point | |
E.5.2 | Secondary end point(s) | 1-Proportion of all adverse events (grade 1-4) including treatment dropout rates. 2- Association of high dose rifampicin with the culture conversion in liquid media at 8 weeks. | |
E.5.2.1 | Timepoint(s) of evaluation of this end point | |
E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | Yes |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | Yes |
E.8.1.7.1 | Other trial design description | |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | Yes |
E.8.2.3.1 | Comparator description | Standard doses of rifampicin | |
E.8.2.4 | Number of treatment arms in the trial | 1 |
E.8.3 | The trial involves single site in the Member State concerned | No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 4 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 4 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | Yes |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned | |
E.8.7 | Trial has a data monitoring committee | No |
E.8.8 | Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial | The last 8-week visit of the last participant undergoing the trial. As TB treatment must continue up to 26 weeks according to WHO guidelines, and there is a high risk of relapse up to 1 year after treatment end, it is usual practice to follow-up TB patients up to 1 year after treatment end (at the same sites involved in the study which are health care public providers). An extended follow up will be offered to participants. | |
E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 1 |
E.8.9.1 | In the Member State concerned months | 6 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 1 |
E.8.9.2 | In all countries concerned by the trial months | 6 |