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Rifampicin at High Dose for Difficult-to-Treat Tuberculosis (RIAlta)

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ClinicalTrials.gov Identifier: NCT04768231
Recruitment Status : Not yet recruiting
First Posted : February 24, 2021
Last Update Posted : February 24, 2021
Sponsor:
Collaborators:
University Medical Center Groningen
Radboud University
Centro Hospitalar De São João, E.P.E.
Instituto Nacional de Enfermedades Respiratorias y del Ambiente, Paraguay
Information provided by (Responsible Party):
Hospital Universitari Vall d'Hebron Research Institute

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.

Condition or disease Intervention/treatment Phase
Tuberculosis Drug: Rifampin Phase 2

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 130 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Intervention Model Description: Single intervention group compared with historical controls
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Safety of Rifampicin at High Dose for the Treatment of Adult Subjects With Complex Drug Susceptible Pulmonary and Extrapulmonary Tuberculosis
Estimated Study Start Date : April 1, 2021
Estimated Primary Completion Date : December 31, 2022
Estimated Study Completion Date : December 31, 2023

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Tuberculosis
Drug Information available for: Rifampin

Arm Intervention/treatment
Experimental: R35HZE
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
The target dose of 35mg/kg will be reached supplementing fixed-dose combination tablets (standard dose) with rifampin-only tablets.
Other Name: Rifampicin




Primary Outcome Measures :
  1. Safety of rifampicin at 35mg/kg/day [ Time Frame: During the first 8 weeks after treatment start ]
    Rate of grade 3 or higher adverse events as compared to that in historical controls


Secondary Outcome Measures :
  1. Efficacy of rifampicin at 35mg/kg/day in pulmonary tuberculosis [ Time Frame: At week 8 after treatment start ]
    Rate of sputum liquid culture conversion (only pulmonary TB participants)

  2. Tolerability of rifampicin at 35mg/kg/day [ Time Frame: During the first 8 weeks after treatment start ]
    Rate of adverse events of any grade as compared to that in historical controls


Other Outcome Measures:
  1. Bactericidal activity in pulmonary tuberculosis [ Time Frame: 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.

  2. Pharmacokinetics of rifampicin: Maximum concentration (Cmax) [ Time Frame: 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.

  3. Pharmacokinetics of rifampicin: Time to maximum concentration (Tmax) [ Time Frame: 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.

  4. Pharmacokinetics of rifampicin: Area Under the Curve (AUC) 0-24 [ Time Frame: 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.

  5. Pharmacogenetics: analyze the variants in SLCO1B1, ABCB1, UGT1A, and PXR genes [ Time Frame: After 4 weeks of treatment ]
    Analyze the polymorphisms in SLCO1B1, ABCB1, UGT1A, and PXR genes and their correlation with pharmacokinetic measures from previous outcomes.

  6. Pharmacodynamics: correlate the AUC0-24/MIC ratio with culture conversion rate [ Time Frame: 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.

  7. AeoNose™ signature during treatment in pulmonary tuberculosis [ Time Frame: 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)

  8. Correlation of AeoNose™ with the bactericidal activity in pulmonary tuberculosis [ Time Frame: 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.

  9. Health Economics [ Time Frame: 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.

  10. Quality of life [ Time Frame: 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

  11. Extended follow-up: safety [ Time Frame: 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.

  12. Extended follow-up: cure, treatment failure, relapse [ Time Frame: 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).



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04768231


Contacts
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Contact: Adrián Sánchez-Montalvá, PhD +34 934893000 ext 6090 adrian.sanchez.montalva@gmail.com
Contact: Juan Espinosa-Pereiro, MD +34 934893000 ext 6090 macspinosa@gmail.com

Locations
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Netherlands
University Medical Center
Groningen, Netherlands, 9700 RB
Contact: Onno W. Akkerman, MD, PhD    +31 643436327    o.w.akkerman@umcg.nl   
Radboud University Medical Center
Nijmegen, Netherlands, 6525 EZ
Contact: Cecile Magis-Escurra, PhD    +31246859770    cecile.magis-escurra@radboudumc.nl   
Paraguay
Instituto Nacional de Enfermedades Respiratorias y del Ambiente
Asunción, Paraguay, 1424
Contact: Arturo Battaglia, MD    +595975443343    arturombc@hotmail.com   
Contact: Gladys Molinas León, MD    +595975443343    gladys_molinasleon@hotmail.com   
Portugal
Centro Hospitalario Universitario de Sao Joao
Porto, Portugal, 4202-451
Contact: Margarida Tavares, MD, MPH    +351 963 565873    margaridaftavares@gmail.com   
Spain
Hospital Universitari Vall d'Hebron. Universitat Autonoma de Barcelona
Barcelona, Spain, 08035
Sponsors and Collaborators
Hospital Universitari Vall d'Hebron Research Institute
University Medical Center Groningen
Radboud University
Centro Hospitalar De São João, E.P.E.
Instituto Nacional de Enfermedades Respiratorias y del Ambiente, Paraguay
Investigators
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Principal Investigator: Adrián Sánchez-Montalvá, PhD Vall d'Hebron University Hospital
Additional Information:
Publications:
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Responsible Party: Hospital Universitari Vall d'Hebron Research Institute
ClinicalTrials.gov Identifier: NCT04768231    
Other Study ID Numbers: RIAlta-1
2020-003146-36 ( EudraCT Number )
First Posted: February 24, 2021    Key Record Dates
Last Update Posted: February 24, 2021
Last Verified: February 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: IPD will be available upn request to the EUSAT-consortium Steering Committee
Supporting Materials: Study Protocol
Statistical Analysis Plan (SAP)
Informed Consent Form (ICF)
Time Frame: Since the end of the study; without specified limit.

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
Keywords provided by Hospital Universitari Vall d'Hebron Research Institute:
Rifampicin
Tuberculosis
Safety
Additional relevant MeSH terms:
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Tuberculosis
Mycobacterium Infections
Actinomycetales Infections
Gram-Positive Bacterial Infections
Bacterial Infections
Bacterial Infections and Mycoses
Infections
Rifampin
Antibiotics, Antitubercular
Antitubercular Agents
Anti-Bacterial Agents
Anti-Infective Agents
Leprostatic Agents
Nucleic Acid Synthesis Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Cytochrome P-450 CYP2B6 Inducers
Cytochrome P-450 Enzyme Inducers
Cytochrome P-450 CYP2C8 Inducers
Cytochrome P-450 CYP2C19 Inducers
Cytochrome P-450 CYP2C9 Inducers
Cytochrome P-450 CYP3A Inducers