Rifampicin at High Dose for Difficult-to-Treat Tuberculosis

Tuberculosis Clinical Trial

— RIAlta  

Official title:

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

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT04768231
• Other study ID #: RIAlta-1
• Secondary ID: 2020-003146-36
• Status: Not yet recruiting
• Phase: Phase 2
• Start date: April 1, 2021
• Est. completion date: December 31, 2023

Study information

• Verified date: February 2021
• Source: Hospital Universitari Vall d'Hebron Research Institute
• Contact: Adrián Sánchez-Montalvá, PhD
• Phone: +34 934893000
• Email: adrian.sanchez.montalva[@]gmail.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 130
• Est. completion date: December 31, 2023
• Est. primary completion date: December 31, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Tuberculosis

Intervention

Drug:
• Rifampin
The target dose of 35mg/kg will be reached supplementing fixed-dose combination tablets (standard dose) with rifampin-only tablets.

Locations

Country	Name	City	State
Netherlands	University Medical Center	Groningen
Netherlands	Radboud University Medical Center	Nijmegen
Paraguay	Instituto Nacional de Enfermedades Respiratorias y del Ambiente	Asunción
Portugal	Centro Hospitalario Universitario de Sao Joao	Porto
Spain	Hospital Universitari Vall d'Hebron. Universitat Autonoma de Barcelona	Barcelona

Sponsors (5)

Lead Sponsor	Collaborator
Hospital Universitari Vall d'Hebron Research Institute	Centro Hospitalar De São João, E.P.E., Instituto Nacional de Enfermedades Respiratorias y del Ambiente, Paraguay, Radboud University, University Medical Center Groningen

Countries where clinical trial is conducted

Netherlands,  Paraguay,  Portugal,  Spain, 

References & Publications (4)

Magis-Escurra C, Later-Nijland HM, Alffenaar JW, Broeders J, Burger DM, van Crevel R, Boeree MJ, Donders AR, van Altena R, van der Werf TS, Aarnoutse RE. Population pharmacokinetics and limited sampling strategy for first-line tuberculosis drugs and moxifloxacin. Int J Antimicrob Agents. 2014 Sep;44(3):229-34. doi: 10.1016/j.ijantimicag.2014.04.019. Epub 2014 Jun 9. — View Citation

Seijger C, Hoefsloot W, Bergsma-de Guchteneire I, Te Brake L, van Ingen J, Kuipers S, van Crevel R, Aarnoutse R, Boeree M, Magis-Escurra C. High-dose rifampicin in tuberculosis: Experiences from a Dutch tuberculosis centre. PLoS One. 2019 Mar 14;14(3):e0213718. doi: 10.1371/journal.pone.0213718. eCollection 2019. — View Citation

Steingart KR, Jotblad S, Robsky K, Deck D, Hopewell PC, Huang D, Nahid P. Higher-dose rifampin for the treatment of pulmonary tuberculosis: a systematic review. Int J Tuberc Lung Dis. 2011 Mar;15(3):305-16. Review. — View Citation

van Ingen J, Aarnoutse RE, Donald PR, Diacon AH, Dawson R, Plemper van Balen G, Gillespie SH, Boeree MJ. Why Do We Use 600 mg of Rifampicin in Tuberculosis Treatment? Clin Infect Dis. 2011 May;52(9):e194-9. doi: 10.1093/cid/cir184. Review. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Bactericidal activity in pulmonary tuberculosis	To describe the rate of sputum smear conversion, decline in bacterial load (measured as logCFU/mL), ant time-to-negative smear and culture.	During the first 8 weeks after treatment start
Other	Pharmacokinetics of rifampicin: Maximum concentration (Cmax)	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.	After 4 weeks of treatment
Other	Pharmacokinetics of rifampicin: Time to maximum concentration (Tmax)	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.	After 4 weeks of treatment
Other	Pharmacokinetics of rifampicin: Area Under the Curve (AUC) 0-24	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.	After 4 weeks of treatment
Other	Pharmacogenetics: analyze the variants in SLCO1B1, ABCB1, UGT1A, and PXR genes	Analyze the polymorphisms in SLCO1B1, ABCB1, UGT1A, and PXR genes and their correlation with pharmacokinetic measures from previous outcomes.	After 4 weeks of treatment
Other	Pharmacodynamics: correlate the AUC0-24/MIC ratio with 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.	After 4 weeks of treatment (AUC0-24/MIC) and 8 weeks (culture conversion rate)
Other	AeoNose™ signature during treatment in pulmonary tuberculosis	Evaluate the response to treatment in the exhaled volatile particles signature by means of an electronic nose device: AeoNose™ (The eNose company, the Netherlands)	Baseline and weeks 1, 2, 4, 6 and 8.
Other	Correlation of AeoNose™ with the bactericidal activity in pulmonary tuberculosis	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.	Baseline and weeks 1, 2, 4, 6 and 8.
Other	Health Economics	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.	During the 6-month standard treatment period.
Other	Quality of life	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	During the 6-month standard treatment period.
Other	Extended follow-up: safety	After the end of the intervention (8 weeks) data will be collected about severe (grade 3 or higher) or serious adverse events.	Up to 12 months after the end of TB treatment.
Other	Extended follow-up: cure, treatment failure, relapse	After the end of the intervention (8 weeks) data will be collected about clinical outcomes as defined by the WHO (cure, treatment failure, relapse).	Up to 12 months after the end of TB treatment.
Primary	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	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
Secondary	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

External Links

•   EUSAT consortium website