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

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

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.

Study Overview

• Status: Not yet recruiting
• Conditions: Tuberculosis
• Intervention / Treatment: Drug: Rifampin

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.

• Study Type: Interventional
• Enrollment (Anticipated): 130
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Adrián Sánchez-Montalvá, PhD; Phone Number: 6090 +34 934893000; Email: adrian.sanchez.montalva@gmail.com
• Study Contact Backup: Name: Juan Espinosa-Pereiro, MD; Phone Number: 6090 +34 934893000; Email: macspinosa@gmail.com

Study Locations

• Netherlands
  • Groningen, Netherlands, 9700 RB
    • University Medical Center
    • Contact: Onno W. Akkerman, MD, PhD; Phone Number: +31 643436327; Email: o.w.akkerman@umcg.nl
  • Nijmegen, Netherlands, 6525 EZ
    • Radboud University Medical Center
    • Contact: Cecile Magis-Escurra, PhD; Phone Number: +31246859770; Email: cecile.magis-escurra@radboudumc.nl
• Paraguay
  • Asunción, Paraguay, 1424
    • Instituto Nacional de Enfermedades Respiratorias y del Ambiente
    • Contact: Arturo Battaglia, MD; Phone Number: +595975443343; Email: arturombc@hotmail.com
    • Contact: Gladys Molinas León, MD; Phone Number: +595975443343; Email: gladys_molinasleon@hotmail.com
• Portugal
  • Porto, Portugal, 4202-451
    • Centro Hospitalario Universitario de Sao Joao
    • Contact: Margarida Tavares, MD, MPH; Phone Number: +351 963 565873; Email: margaridaftavares@gmail.com
• Spain
  • Barcelona, Spain, 08035
    • Hospital Universitari Vall d'Hebron. Universitat Autonoma de Barcelona

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / 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 Names: Rifampicin

What is the study measuring?

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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
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
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
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
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
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
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)
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.
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.
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.
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.
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.
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.

Collaborators and Investigators

• Sponsor: Hospital Universitari Vall d'Hebron Research Institute
• Collaborators: Radboud University Medical Center; University Medical Center Groningen; Centro Hospitalar De São João, E.P.E.; Instituto Nacional de Enfermedades Respiratorias y del Ambiente, Paraguay
• Investigators: Principal Investigator: Adrián Sánchez-Montalvá, PhD, Vall D'Hebron University Hospital

Publications and helpful links

General Publications

• 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.
• 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.
• 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.
• 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.

Helpful Links

• EUSAT consortium website

Study record dates

Study Major Dates

• Study Start (Anticipated): April 1, 2021
• Primary Completion (Anticipated): December 31, 2022
• Study Completion (Anticipated): December 31, 2023

Study Registration Dates

• First Submitted: February 15, 2021
• First Submitted That Met QC Criteria: February 22, 2021
• First Posted (Actual): February 24, 2021

Study Record Updates

• Last Update Posted (Actual): February 24, 2021
• Last Update Submitted That Met QC Criteria: February 22, 2021
• Last Verified: February 1, 2021

More Information

Terms related to this study

• Keywords: Safety; Tuberculosis; Rifampicin
• Additional Relevant MeSH Terms: Infections; Bacterial Infections; Bacterial Infections and Mycoses; Gram-Positive Bacterial Infections; Actinomycetales Infections; Mycobacterium Infections; Tuberculosis; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Anti-Bacterial Agents; Leprostatic Agents; Cytochrome P-450 Enzyme Inducers; Cytochrome P-450 CYP3A Inducers; Antitubercular Agents; Antibiotics, Antitubercular; Cytochrome P-450 CYP2B6 Inducers; Cytochrome P-450 CYP2C8 Inducers; Cytochrome P-450 CYP2C19 Inducers; Cytochrome P-450 CYP2C9 Inducers; Rifampin
• Other Study ID Numbers: RIAlta-1; 2020-003146-36 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD Plan Description: IPD will be available upn request to the EUSAT-consortium Steering Committee
• IPD Sharing Time Frame: Since the end of the study; without specified limit.
• IPD Sharing Supporting Information Type: Study Protocol; Statistical Analysis Plan (SAP); Informed Consent Form (ICF)

Drug and device information, study documents

• 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