Rifampicin at High Dose for Difficult-to-Treat Tuberculosis

Study Overview
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Brief Summary
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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
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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.

Official Title
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Safety of Rifampicin at High Dose for the Treatment of Adult Subjects With Complex Drug Susceptible Pulmonary and Extrapulmonary Tuberculosis

Conditions
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Tuberculosis

Intervention / Treatment
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* Drug: Rifampin


Participation Criteria
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Eligibility Criteria
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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: 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. AND Age ≥ 60 years old. OR Age ≥ 18 years AND one of the following 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 Exclusion criteria: Subjects will be excluded from entry if ANY ONE of the criteria listed below is met: Rifampicin resistance confirmation. Barthel index <40 for subjects older than 60 years old. 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. Subjects with known allergy or sensitivity to rifampicin, or any of the other components of DS-TB treatment. 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. 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. Positive pregnancy test Breastfeeding women. 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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Interventional Model Description: Single intervention group compared with historical controls
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: R35HZE<br>Participants treated with rifampicin at a dose of 35 mg per kilogram of body weight per day, added to the standard doses of isoniazid, pyrazinamide and ethambutol. | Drug: Rifampin<br>* The target dose of 35mg/kg will be reached supplementing fixed-dose combination tablets (standard dose) with rifampin-only tablets.<br>* Other names: Rifampicin;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety of rifampicin at 35mg/kg/day | Rate of grade 3 or higher adverse events as compared to that in historical controls | During the first 8 weeks after treatment start | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Efficacy of rifampicin at 35mg/kg/day in pulmonary tuberculosis | Rate of sputum liquid culture conversion (only pulmonary TB participants) | At week 8 after treatment start | 
| Tolerability of rifampicin at 35mg/kg/day | Rate of adverse events of any grade as compared to that in historical controls | During the first 8 weeks after treatment start | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Rifampicin, Tuberculosis, Safety