search
Back to results

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

Primary Purpose

Tuberculosis

Status
Not yet recruiting
Phase
Phase 2
Locations
International
Study Type
Interventional
Intervention
Rifampin
Sponsored by
Hospital Universitari Vall d'Hebron Research Institute
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Tuberculosis focused on measuring Rifampicin, Tuberculosis, Safety

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

  • University Medical Center
  • Radboud University Medical Center
  • Instituto Nacional de Enfermedades Respiratorias y del Ambiente
  • Centro Hospitalario Universitario de Sao Joao
  • Hospital Universitari Vall d'Hebron. Universitat Autonoma de Barcelona

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

R35HZE

Arm Description

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.

Outcomes

Primary Outcome Measures

Safety of rifampicin at 35mg/kg/day
Rate of grade 3 or higher adverse events as compared to that in historical controls

Secondary Outcome Measures

Efficacy of rifampicin at 35mg/kg/day in pulmonary tuberculosis
Rate of sputum liquid culture conversion (only pulmonary TB participants)
Tolerability of rifampicin at 35mg/kg/day
Rate of adverse events of any grade as compared to that in historical controls

Full Information

First Posted
February 15, 2021
Last Updated
February 22, 2021
Sponsor
Hospital Universitari Vall d'Hebron Research Institute
Collaborators
University Medical Center Groningen, Radboud University Medical Center, Centro Hospitalar De São João, E.P.E., Instituto Nacional de Enfermedades Respiratorias y del Ambiente, Paraguay
search

1. Study Identification

Unique Protocol Identification Number
NCT04768231
Brief Title
Rifampicin at High Dose for Difficult-to-Treat Tuberculosis
Acronym
RIAlta
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

2. Study Status

Record Verification Date
February 2021
Overall Recruitment Status
Not yet recruiting
Study Start Date
April 1, 2021 (Anticipated)
Primary Completion Date
December 31, 2022 (Anticipated)
Study Completion Date
December 31, 2023 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Hospital Universitari Vall d'Hebron Research Institute
Collaborators
University Medical Center Groningen, Radboud University Medical Center, Centro Hospitalar De São João, E.P.E., Instituto Nacional de Enfermedades Respiratorias y del Ambiente, Paraguay

4. Oversight

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
Data Monitoring Committee
Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Tuberculosis
Keywords
Rifampicin, Tuberculosis, Safety

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Model Description
Single intervention group compared with historical controls
Masking
None (Open Label)
Allocation
N/A
Enrollment
130 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
R35HZE
Arm Type
Experimental
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
Rifampin
Other Intervention Name(s)
Rifampicin
Intervention Description
The target dose of 35mg/kg will be reached supplementing fixed-dose combination tablets (standard dose) with rifampin-only tablets.
Primary Outcome Measure Information:
Title
Safety of rifampicin at 35mg/kg/day
Description
Rate of grade 3 or higher adverse events as compared to that in historical controls
Time Frame
During the first 8 weeks after treatment start
Secondary Outcome Measure Information:
Title
Efficacy of rifampicin at 35mg/kg/day in pulmonary tuberculosis
Description
Rate of sputum liquid culture conversion (only pulmonary TB participants)
Time Frame
At week 8 after treatment start
Title
Tolerability of rifampicin at 35mg/kg/day
Description
Rate of adverse events of any grade as compared to that in historical controls
Time Frame
During the first 8 weeks after treatment start
Other Pre-specified Outcome Measures:
Title
Bactericidal activity in pulmonary tuberculosis
Description
To describe the rate of sputum smear conversion, decline in bacterial load (measured as logCFU/mL), ant time-to-negative smear and culture.
Time Frame
During the first 8 weeks after treatment start
Title
Pharmacokinetics of rifampicin: Maximum concentration (Cmax)
Description
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.
Time Frame
After 4 weeks of treatment
Title
Pharmacokinetics of rifampicin: Time to maximum concentration (Tmax)
Description
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.
Time Frame
After 4 weeks of treatment
Title
Pharmacokinetics of rifampicin: Area Under the Curve (AUC) 0-24
Description
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.
Time Frame
After 4 weeks of treatment
Title
Pharmacogenetics: analyze the variants in SLCO1B1, ABCB1, UGT1A, and PXR genes
Description
Analyze the polymorphisms in SLCO1B1, ABCB1, UGT1A, and PXR genes and their correlation with pharmacokinetic measures from previous outcomes.
Time Frame
After 4 weeks of treatment
Title
Pharmacodynamics: correlate the AUC0-24/MIC ratio with culture conversion rate
Description
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.
Time Frame
After 4 weeks of treatment (AUC0-24/MIC) and 8 weeks (culture conversion rate)
Title
AeoNose™ signature during treatment in pulmonary tuberculosis
Description
Evaluate the response to treatment in the exhaled volatile particles signature by means of an electronic nose device: AeoNose™ (The eNose company, the Netherlands)
Time Frame
Baseline and weeks 1, 2, 4, 6 and 8.
Title
Correlation of AeoNose™ with the bactericidal activity in pulmonary tuberculosis
Description
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.
Time Frame
Baseline and weeks 1, 2, 4, 6 and 8.
Title
Health Economics
Description
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.
Time Frame
During the 6-month standard treatment period.
Title
Quality of life
Description
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
Time Frame
During the 6-month standard treatment period.
Title
Extended follow-up: safety
Description
After the end of the intervention (8 weeks) data will be collected about severe (grade 3 or higher) or serious adverse events.
Time Frame
Up to 12 months after the end of TB treatment.
Title
Extended follow-up: cure, treatment failure, relapse
Description
After the end of the intervention (8 weeks) data will be collected about clinical outcomes as defined by the WHO (cure, treatment failure, relapse).
Time Frame
Up to 12 months after the end of TB treatment.

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
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: 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) Central Nervous System TB involvement Exclusion criteria: 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. 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. Positive pregnancy test Breastfeeding women. 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.
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Adrián Sánchez-Montalvá, PhD
Phone
+34 934893000
Ext
6090
Email
adrian.sanchez.montalva@gmail.com
First Name & Middle Initial & Last Name or Official Title & Degree
Juan Espinosa-Pereiro, MD
Phone
+34 934893000
Ext
6090
Email
macspinosa@gmail.com
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Adrián Sánchez-Montalvá, PhD
Organizational Affiliation
Vall d'Hebron University Hospital
Official's Role
Principal Investigator
Facility Information:
Facility Name
University Medical Center
City
Groningen
ZIP/Postal Code
9700 RB
Country
Netherlands
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Onno W. Akkerman, MD, PhD
Phone
+31 643436327
Email
o.w.akkerman@umcg.nl
Facility Name
Radboud University Medical Center
City
Nijmegen
ZIP/Postal Code
6525 EZ
Country
Netherlands
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Cecile Magis-Escurra, PhD
Phone
+31246859770
Email
cecile.magis-escurra@radboudumc.nl
Facility Name
Instituto Nacional de Enfermedades Respiratorias y del Ambiente
City
Asunción
ZIP/Postal Code
1424
Country
Paraguay
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Arturo Battaglia, MD
Phone
+595975443343
Email
arturombc@hotmail.com
First Name & Middle Initial & Last Name & Degree
Gladys Molinas León, MD
Phone
+595975443343
Email
gladys_molinasleon@hotmail.com
Facility Name
Centro Hospitalario Universitario de Sao Joao
City
Porto
ZIP/Postal Code
4202-451
Country
Portugal
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Margarida Tavares, MD, MPH
Phone
+351 963 565873
Email
margaridaftavares@gmail.com
Facility Name
Hospital Universitari Vall d'Hebron. Universitat Autonoma de Barcelona
City
Barcelona
ZIP/Postal Code
08035
Country
Spain

12. IPD Sharing Statement

Plan to Share IPD
Yes
IPD Sharing 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.
Citations:
PubMed Identifier
21467012
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.
Results Reference
background
PubMed Identifier
30870476
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.
Results Reference
background
PubMed Identifier
21333096
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.
Results Reference
background
PubMed Identifier
24985091
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.
Results Reference
background
Links:
URL
http://www.eusattb.net/
Description
EUSAT consortium website

Learn more about this trial

Rifampicin at High Dose for Difficult-to-Treat Tuberculosis

We'll reach out to this number within 24 hrs