Rifampicin at High Dose for Difficult-to-Treat Tuberculosis

NCT04768231 | Unknown Phase 2 DMC

• 2 other identifiers: RIAlta-12020-003146-36
• Study Type: interventional
• Target: 130
• Locations: 4 countries
• Sites: 5

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.

Conditions

Tuberculosis

Keywords

Rifampicin; Tuberculosis; Safety

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (2)

• Efficacy of rifampicin at 35mg/kg/day in pulmonary tuberculosis

  At week 8 after treatment start

• Tolerability of rifampicin at 35mg/kg/day

  During the first 8 weeks after treatment start

Other Outcomes (12)

• Bactericidal activity in pulmonary tuberculosis

  During the first 8 weeks after treatment start

• Pharmacokinetics of rifampicin: Maximum concentration (Cmax)

  After 4 weeks of treatment

• Pharmacokinetics of rifampicin: Time to maximum concentration (Tmax)

  After 4 weeks of treatment

Study Arms (1)

R35HZE

EXPERIMENTAL

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

Interventions

Rifampin DRUG

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

Also known as: Rifampicin

R35HZE

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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)

You may not qualify if:

• 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.

Sponsors & Collaborators

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

Study Sites (5)

University Medical Center

Groningen, 9700 RB, Netherlands

Location

Radboud University Medical Center

Nijmegen, 6525 EZ, Netherlands

Location

Instituto Nacional de Enfermedades Respiratorias y del Ambiente

Asunción, 1424, Paraguay

Location

Centro Hospitalario Universitario de Sao Joao

Porto, 4202-451, Portugal

Location

Hospital Universitari Vall d'Hebron. Universitat Autonoma de Barcelona

Barcelona, 08035, Spain

Location

Related Publications (5)

• 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.

  PMID: 21467012 BACKGROUND

• 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.

  PMID: 30870476 BACKGROUND

• 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.

  PMID: 21333096 BACKGROUND

• 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.

  PMID: 24985091 BACKGROUND

• Espinosa-Pereiro J, Ghimire S, Sturkenboom MGG, Alffenaar JC, Tavares M, Aguirre S, Battaglia A, Molinas G, Tortola T, Akkerman OW, Sanchez-Montalva A, Magis-Escurra C. Safety of Rifampicin at High Dose for Difficult-to-Treat Tuberculosis: Protocol for RIAlta Phase 2b/c Trial. Pharmaceutics. 2022 Dec 20;15(1):9. doi: 10.3390/pharmaceutics15010009.

  PMID: 36678638 DERIVED

Related Links

• EUSAT consortium website

MeSH Terms

Conditions

Tuberculosis

Interventions

Rifampin

Condition Hierarchy (Ancestors)

Mycobacterium Infections; Actinomycetales Infections; Gram-Positive Bacterial Infections; Bacterial Infections; Bacterial Infections and Mycoses; Infections

Intervention Hierarchy (Ancestors)

Rifamycins; Heterocyclic Compounds, 4 or More Rings; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Lactams, Macrocyclic; Macrocyclic Compounds; Polycyclic Compounds

Study Officials

• Adrián Sánchez-Montalvá, PhD

  Vall d'Hebron University Hospital

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Adrián Sánchez-Montalvá, PhD

CONTACT

+34 934893000; adrian.sanchez.montalva@gmail.com

Juan Espinosa-Pereiro, MD

CONTACT

+34 934893000; macspinosa@gmail.com

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Single intervention group compared with historical controls

Study Record Dates

• First Submitted: February 15, 2021
• First Posted: February 24, 2021
• Study Start: April 1, 2021
• Primary Completion: December 31, 2022
• Study Completion: December 31, 2023
• Last Updated: February 24, 2021

Record last verified: 2021-02

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF
• Time Frame: Since the end of the study; without specified limit.

Locations

PA (1); ES (1); PT (1); NL (2)