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

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Fundacio Hospital Universitari Vall D’Hebron Institut De Recerca

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Bacterial Infections and Mycoses [C01]

Trial duration

4 Feb 2025 → ongoing

Decision date (initial)

2025-02-04

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

Funding sources

Radboud university medical centre · University Medical Centre Groningen · INERAM · EUSAT project (EU funded) · Vall d'Hebron Institute of Research

External identifiers

EU CT number

2024-519983-42-00

EudraCT number

2020-003146-36

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety

To evaluate the safety of high-dose rifampicin (35 mg/kg/d) supplemented with standard doses of isoniazid, pyrazinamide, and ethambutol for 8 weeks in adult subjects with pulmonary or extrapulmonary DS-TB belonging to difficult to treat subgroups.
• Safety will be defined based on the proportion of participants experiencing severe adverse events (grade 3 or superior according to the Common Terminology Criteria for Adverse Events, CTCAE version 5) compared to historical controls on 10mg/kg/day of rifampicin.

Secondary objectives 10

1. 1. To evaluate the tolerability of high-dose rifampicin (35 mg/kg/day) supplemented with standard doses of isoniazid, pyrazinamide, and ethambutol for 8 weeks in adult subjects with pulmonary or extrapulmonary TB belonging to difficult to treat patient subgroups. o Tolerability will be defined based on the proportion of all adverse events (grade 1-4) including treatment dropout rates.
2. 2. To evaluate the efficacy of high dose rifampicin (35 mg/kg/day) supplemented with standard doses of isoniazid, pyrazinamide, and ethambutol for 8 weeks by assessing early sterilizing activity in the sputum of pulmonary TB subjects belonging to difficult to treat patient subgroups. o The efficacy will be assessed based on association of high dose rifampicin with the culture conversion in liquid media at 8 weeks.
3. 3. To describe the bactericidal activity as the proportion of sputum smear conversion at 8 weeks.
4. 4. To describe the time dynamics of sputum smear bacterial load decline, smear and culture conversion.
5. 5. To compare the relapse rate 1 year after treatment completion (extended follow up).
6. 6. To describe pharmacokinetics-pharmacodynamics (PK/PD) of rifampicin at high doses in difficult-to-treat pulmonary and extrapulmonary TB.
7. 7. To describe the association between genetic polymorphisms and differences in AUC of rifampicin.
8. 8. To analyze the correlation between rifampicin’s AUC/MIC values and the efficacy outcomes.
9. 9. To evaluate the response to treatment as measured by exhaled VOCs.
10. 10. To describe tuberculosis associated costs and the quality of life of DS-TB participants.

Conditions and MedDRA coding

TUBERCULOSIS

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 5

1. 1. Subjects with confirmed or probable pulmonary or extra pulmonary DS-TB.
2. 2. Informed consent provided.
3. 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. 4. Female participants of childbearing age must have a negative pregnancy test at baseline.
5. 5. Age ≥ 60 years old; or Age ≥ 18 years and any of the followings: 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 14

1. 1. Rifampicin resistance confirmation.
2. 2. Barthel index <40 for subjects older than 60 years old.
3. 3. Signs of significant liver disease: o Liver enzymes (AST or ALT) > 5x upper limit of normal o Total bilirubin > 3x upper limit of normal o Subjects with a Child-Pugh grade C cirrhosis or acute decompensation of their chronic liver disease at enrolment. o Any other grade 3-4 hepatobiliary alteration according to the CTCAE v5.
4. 4. Subjects with known allergy or sensitivity to rifampicin, or any of the other components of DS-TB treatment.
5. 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. 6. The subject is enrolled in any other investigational trial that includes a drug intervention.
7. 7. Subjects with solid organ transplantation or bone marrow transplantation.
8. 8. Subjects with an active onco-hematological neoplasm requiring chemotherapy or immune therapy.
9. 9. Previous severe pulmonary disease, other than pulmonary DS-TB, according to local investigator.
10. 10. Pre-existing epilepsy or psychiatric disorder according to local investigator.
11. 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. 12. Positive pregnancy test
13. 13. Breastfeeding women.
14. 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.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. proportion of participants with one or more SAE (i.e. grade 3 or 4 AE) at 8 weeks of treatment

Secondary endpoints 5

1. Eficaccy: The proportion of participants with a favorable outcome at 8 weeks of treatment
2. Tolerability: proportion of participants having one or more AE in the prospective cohort.
3. efficacy: time to sputum culture conversion from positive to negative
4. Correlation of the AUC/MIC values with time to sputum culture conversion adjusted with other explanatory covariates
5. changes in quality of life questionnaires and in TB associated costs from all sites will be depicted

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 2

Auxiliary 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Fundacio Hospital Universitari Vall D’Hebron Institut De Recerca

Sponsor organisation

Fundacio Hospital Universitari Vall D’Hebron Institut De Recerca

Address

Passeig De La Vall D'Hebron 119-129

City

Barcelona

Postcode

08035

Country

Spain

Scientific contact point

Organisation

Fundacio Hospital Universitari Vall D’Hebron Institut De Recerca

Contact name

ADRIÁN SÁNCHEZ MONTALVÁ

Public contact point

Organisation

Fundacio Hospital Universitari Vall D’Hebron Institut De Recerca

Contact name

ADRIÁN SÁNCHEZ MONTALVÁ

Locations

2 EU/EEA countries · 2 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 13 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

1 submissions — initial application plus substantial / non-substantial modifications