Tuberculosis
Conditions
Keywords
Rifampicin, Tuberculosis, Safety
Brief summary
The purpose of this study is to assess the safety of rifampicin given at a dose three times as the standard one, in persons with tuberculosis that belong to groups that have not been widely included in previous trials.
Detailed description
A prospective, one-arm, open-label trial to evaluate the safety of rifampicin at 35mg/kg per day, added to the remaining standard first-line drugs, in subjects with tuberculosis belonging to groups that have been underrepresented in previous trials: persons living with HIV, older than 65 years, malnourished, diabetics, and chronic stable liver disease. The main outcome is the rate of severe adverse events and adverse events leading to treatment modification as compared to that in a historical cohort (patietns belonging to these groups treated in the same centers from 2017-2019). Microbiological efficacy and extended follow-up data until one year after treatment will also be collected.
Interventions
DRUGRifampin
The target dose of 35mg/kg will be reached supplementing fixed-dose combination tablets (standard dose) with rifampin-only tablets.
Sponsors
University Medical Center Groningen
Radboud University Medical Center
Centro Hospitalar De São João, E.P.E.
Instituto Nacional de Enfermedades Respiratorias y del Ambiente, Paraguay
Hospital Universitari Vall d'Hebron Research Institute
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Single intervention group compared with historical controls
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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 or anti-core antibodies) 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
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 significant liver disease: * Liver enzymes (AST or ALT) \> 5x upper limit of normal * Total bilirubin \> 3x upper limit of normal * Subjects with a Child-Pugh grade C cirrhosis or acute decompensation of their chronic liver disease at enrolment. * Any other grade 3-4 hepatobiliary alteration according to the CTCAE v5. 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 requiring chemotherapy or immune therapy. 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 table 2.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Safety of rifampicin at 35mg/kg/day | During the first 8 weeks after treatment start | Rate of grade 3 or higher adverse events as compared to that in historical controls |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Efficacy of rifampicin at 35mg/kg/day in pulmonary tuberculosis | At week 8 after treatment start | Rate of sputum liquid culture conversion (only pulmonary TB participants) |
| Tolerability of rifampicin at 35mg/kg/day | During the first 8 weeks after treatment start | Rate of adverse events of any grade as compared to that in historical controls |
Other
| Measure | Time frame | Description |
|---|---|---|
| Pharmacokinetics of rifampicin: Area Under the Curve (AUC) 0-24 | After 4 weeks of treatment | To describe the AUC0-24 of rifampicin at 35mg/kg in the population included in the study. A spare-sample strategy sill be used with blood samples taken at 2, 4, and 6 hours after rifampicin administration. The AUC 0-24h will be modelled accodring to the methods described in Magis-Escurrra et al, 2014. |
| Pharmacogenetics: analyze the variants in SLCO1B1, ABCB1, UGT1A, and PXR genes | After 4 weeks of treatment | Analyze the polymorphisms in SLCO1B1, ABCB1, UGT1A, and PXR genes and their correlation with pharmacokinetic measures from previous outcomes. |
| Pharmacodynamics: correlate the AUC0-24/MIC ratio with culture conversion rate | After 4 weeks of treatment (AUC0-24/MIC) and 8 weeks (culture conversion rate) | Correlate the pharmacokinetic measure AUC0-24 to the MIC (Minimum Inhibitory Concentration) ratio with the rate of culture conversion of sputum sample at 8 weeks in liquid culture medium. |
| AeoNose™ signature during treatment in pulmonary tuberculosis | Baseline and weeks 1, 2, 4, 6 and 8. | Evaluate the response to treatment in the exhaled volatile particles signature by means of an electronic nose device: AeoNose™ (The eNose company, the Netherlands) |
| Bactericidal activity in pulmonary tuberculosis | During the first 8 weeks after treatment start | To describe the rate of sputum smear conversion, decline in bacterial load (measured as logCFU/mL), ant time-to-negative smear and culture. |
| Health Economics | During the 6-month standard treatment period. | To describe tuberculosis associated costs and the incidence of catastrophic costs using the EUSAT-RCS questionnaire based on the WHO handbook for economic studies in tuberculosis in a subgroup of the participants. |
| Quality of life | During the 6-month standard treatment period. | To describe the changes in quality of life during tuberculosis treatment using the SF-12 questionnaire and the St George's respiratory questionnaire (for pulmonary TB participants) of a subgroup of the included participants |
| Extended follow-up: safety | Up to 12 months after the end of TB treatment. | After the end of the intervention (8 weeks) data will be collected about severe (grade 3 or higher) or serious adverse events. |
| Extended follow-up: cure, treatment failure, relapse | Up to 12 months after the end of TB treatment. | After the end of the intervention (8 weeks) data will be collected about clinical outcomes as defined by the WHO (cure, treatment failure, relapse). |
| Correlation of AeoNose™ with the bactericidal activity in pulmonary tuberculosis | Baseline and weeks 1, 2, 4, 6 and 8. | Correlation of the changes in signature by means of an AeoNose™ and the changes in bacillary load during the first 8 weeks of treatment and the culture conversion rate at 8 weeks. |
| Pharmacokinetics of rifampicin: Maximum concentration (Cmax) | After 4 weeks of treatment | To describe the Camx of rifampicin at 35mg/kg in the population included in the study. A spare-sample strategy sill be used with blood samples taken at 2, 4, and 6 hours after rifampicin administration. |
| Pharmacokinetics of rifampicin: Time to maximum concentration (Tmax) | After 4 weeks of treatment | To describe the Tmax of rifampicin at 35mg/kg in the population included in the study. A spare-sample strategy sill be used with blood samples taken at 2, 4, and 6 hours after rifampicin administration. |
Countries
Netherlands, Paraguay, Portugal, Spain
Contacts
Primary ContactAdrián Sánchez-Montalvá, PhD
Backup ContactJuan Espinosa-Pereiro, MD
Outcome results
None listed