Clinical trial NCT04768231: Rifampicin at High Dose for Difficult-to-Treat Tuberculosis
Official title: Safety of Rifampicin at High Dose for the Treatment of Adult Subjects With Complex Drug Susceptible Pulmonary and Extrapulmonary Tuberculosis
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE2
Conditions: Tuberculosis
Keywords: Rifampicin
Tuberculosis
Safety
Lead sponsor: Hospital Universitari Vall d'Hebron Research Institute
Sponsor class: OTHER
Collaborators: name: University Medical Center Groningen
name: Radboud University Medical Center
name: Centro Hospitalar De São João, E.P.E.
name: Instituto Nacional de Enfermedades Respiratorias y del Ambiente, Paraguay
First posted: 2021-02-24
Enrollment: 130
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Intervention model description: Single intervention group compared with historical controls
Primary purpose: TREATMENT

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Safety of rifampicin at 35mg/kg/day
timeFrame: During the first 8 weeks after treatment start
Secondary outcomes:
measure: Efficacy of rifampicin at 35mg/kg/day in pulmonary tuberculosis
timeFrame: At week 8 after treatment start
measure: Tolerability of rifampicin at 35mg/kg/day
timeFrame: During the first 8 weeks after treatment start
Other outcomes:
measure: Bactericidal activity in pulmonary tuberculosis
timeFrame: During the first 8 weeks after treatment start
measure: Pharmacokinetics of rifampicin: Maximum concentration (Cmax)
timeFrame: After 4 weeks of treatment
measure: Pharmacokinetics of rifampicin: Time to maximum concentration (Tmax)
timeFrame: After 4 weeks of treatment
measure: Pharmacokinetics of rifampicin: Area Under the Curve (AUC) 0-24
timeFrame: After 4 weeks of treatment
measure: Pharmacogenetics: analyze the variants in SLCO1B1, ABCB1, UGT1A, and PXR genes
timeFrame: After 4 weeks of treatment
measure: Pharmacodynamics: correlate the AUC0-24/MIC ratio with culture conversion rate
timeFrame: After 4 weeks of treatment (AUC0-24/MIC) and 8 weeks (culture conversion rate)
measure: AeoNose™ signature during treatment in pulmonary tuberculosis
timeFrame: Baseline and weeks 1, 2, 4, 6 and 8.
measure: Correlation of AeoNose™ with the bactericidal activity in pulmonary tuberculosis
timeFrame: Baseline and weeks 1, 2, 4, 6 and 8.
measure: Health Economics
timeFrame: During the 6-month standard treatment period.
measure: Quality of life
timeFrame: During the 6-month standard treatment period.
measure: Extended follow-up: safety
timeFrame: Up to 12 months after the end of TB treatment.
measure: Extended follow-up: cure, treatment failure, relapse
timeFrame: Up to 12 months after the end of TB treatment.
Locations:
city: Groningen
country: Netherlands
facility: University Medical Center
city: Nijmegen
country: Netherlands
facility: Radboud University Medical Center
city: Asunción
country: Paraguay
facility: Instituto Nacional de Enfermedades Respiratorias y del Ambiente
city: Porto
country: Portugal
facility: Centro Hospitalario Universitario de Sao Joao
city: Barcelona
country: Spain
facility: Hospital Universitari Vall d'Hebron. Universitat Autonoma de Barcelona
Study officials:
affiliation: Vall d'Hebron University Hospital
name: Adrián Sánchez-Montalvá, PhD
role: PRINCIPAL_INVESTIGATOR
References:
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.
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.
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.
citation: 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.