TuberculosisPhase 2RIAltaNCT04768231
Rifampicin at High Dose for Difficult-to-Treat Tuberculosis
A Phase 2 study testing Rifampin in people with Tuberculosis, run by Hospital Universitari Vall d'Hebron Research Institute at 5 sites in 4 countries.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Tuberculosis
- What is being tested?
- Rifampin
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 130 participants
- Where
- 5 sitesin 4 countries
- Study dates
- 1 Apr 2021to 31 Dec 2023
- Phase
- Phase 2
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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
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- 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
Who cannot join
- 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
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- 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.
Trial locations and contacts
5 sites in 4 countries.
5 sites in 4 countries
Netherlands2 sites
University Medical Center
Groningen, 9700 RB
Onno W. Akkerman, MD, PhD, +31 643436327, o.w.akkerman@umcg.nl
Radboud University Medical Center
Nijmegen, 6525 EZ
Cecile Magis-Escurra, PhD, +31246859770, cecile.magis-escurra@radboudumc.nl
Paraguay1 site
Instituto Nacional de Enfermedades Respiratorias y del Ambiente
Asunción, 1424
Arturo Battaglia, MD, +595975443343, arturombc@hotmail.com
Gladys Molinas León, MD, +595975443343, gladys_molinasleon@hotmail.com
Portugal1 site
Centro Hospitalario Universitario de Sao Joao
Porto, 4202-451
Margarida Tavares, MD, MPH, +351 963 565873, margaridaftavares@gmail.com
Spain1 site
Hospital Universitari Vall d'Hebron. Universitat Autonoma de Barcelona
Barcelona, 08035
About this study
Official title: 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.
Read the 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.
- Conditions
- Tuberculosis
- Being tested
- Rifampin
- Keywords
- Rifampicin, Tuberculosis, Safety
- Medical subject headings
- Tuberculosis
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
RifampinDrug
Also called Rifampicin
The target dose of 35mg/kg will be reached supplementing fixed-dose combination tablets (standard dose) with rifampin-only tablets.
| Study group | Role | What they receive |
|---|---|---|
| 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. Receives: Drug: Rifampin |
What is being measured
The primary outcome is the main question the study is designed to answer.
Safety of rifampicin at 35mg/kg/day
Rate of grade 3 or higher adverse events as compared to that in historical controls
Measured: During the first 8 weeks after treatment start
Secondary outcomes (2)
Efficacy of rifampicin at 35mg/kg/day in pulmonary tuberculosis
Rate of sputum liquid culture conversion (only pulmonary TB participants)
Measured: 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
Measured: During the first 8 weeks after treatment start
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted24 Feb 2021
- Study start1 Apr 2021 (estimated)
- Primary completion31 Dec 2022 (estimated)
- Study completion31 Dec 2023 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (5)Papers the sponsor has linked to this study.
- Other trials for TuberculosisStudies of the same condition, open and under way.
- More trials run by Hospital Universitari Vall d'Hebron Research InstituteThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Model description
- Single intervention group compared with historical controls
- Masking
- None (open label)
- Enrolment
- 130 participants (estimated)
Sponsor and investigators
- Sponsor type
- University, hospital or other
- 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
- Responsible party
- Sponsor
- Investigators
- Adrián Sánchez-Montalvá, PhD, Principal investigator, Vall d'Hebron University Hospital
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04768231
- Sponsor's protocol ID
- RIAlta-1
- Other IDs
- 2020-003146-36
- Acronym
- RIAlta
- Status last verified
- Feb 2021
- First submitted
- 15 Feb 2021
- Last updated
- 24 Feb 2021
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- Yes: IPD will be available upn request to the EUSAT-consortium Steering Committee
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.
PubMed 21467012Seijger 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.
PubMed 30870476Steingart 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.
PubMed 21333096Magis-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.
PubMed 24985091Espinosa-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.
PubMed 36678638
Study at a glance
From the registry record, last updated by the sponsor on 24 Feb 2021. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Safety of Rifampicin at High Dose for the Treatment of Adult Subjects With Complex Drug Susceptible Pulmonary and Extrapulmonary Tuberculosis
- ClinicalTrials.gov ID
- NCT04768231
- Acronym / sponsor ID
- RIAlta / RIAlta-1
- Conditions
- Tuberculosis
- Keywords
- Rifampicin, Tuberculosis, Safety
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Unknown status
- Enrolment
- 130 participants (estimated)
- Lead sponsor
- Hospital Universitari Vall d'Hebron Research InstituteUniversity, hospital or other
- 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
- Study start
- 1 Apr 2021 (estimated)
- Primary completion
- 31 Dec 2022 (estimated)
- Study completion
- 31 Dec 2023 (estimated)
- First posted
- 24 Feb 2021 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
- Model description
- Single intervention group compared with historical controls
| Arm | Type | Receives |
|---|---|---|
| R35HZE | Experimental | Drug: RifampinParticipants 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. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (16 listed)
- 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.
Key exclusion criteria (19 listed)
- Rifampicin resistance confirmation.
- Barthel index <40 for subjects older than 60 years old.
- Signs of significant liver disease:
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| RifampinAlso: RifampicinThe target dose of 35mg/kg will be reached supplementing fixed-dose combination tablets (standard dose) with rifampin-only tablets. | Drug | R35HZE |
Primary outcome
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
2 secondary outcomes
Efficacy of rifampicin at 35mg/kg/day in pulmonary tuberculosis
Time frame: At week 8 after treatment start
Tolerability of rifampicin at 35mg/kg/day
Time frame: During the first 8 weeks after treatment start
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 24 Feb 2021.
- Background: PubMed 21467012van 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.
- Background: PubMed 30870476Seijger 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.
- Background: PubMed 21333096Steingart 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.
- Background: PubMed 24985091Magis-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.
- Derived from this study: PubMed 36678638Espinosa-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.
- EUSAT consortium websiteLink provided by the sponsor.
- Individual participant dataSharing planned: Yes. IPD will be available upn request to the EUSAT-consortium Steering Committee
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Adrián Sánchez-Montalvá, PhD principal investigator
Vall d'Hebron University Hospital
5 sites in 4 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Rifampin in people with Tuberculosis, run by Hospital Universitari Vall d'Hebron Research Institute at 5 sites in 4 countries.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 16 inclusion and 19 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: status not confirmed, as of the sponsor's last update on 24 Feb 2021. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 5 sites in Netherlands, Paraguay, Portugal, Spain. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
Contact Adrián Sánchez-Montalvá, PhD (+34 934893000 ext. 6090, adrian.sanchez.montalva@gmail.com), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Safety of rifampicin at 35mg/kg/day (time frame: During the first 8 weeks after treatment start). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT04768231, which also lists 5 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 24 Feb 2021; AzTrials last refreshed its copy on 6 Nov 2026.