Tuberculous MeningitisPhase 2REMOVERNCT01802502
Rifampicin Explorative PK Study for Tuberculous Meningitis Comparing Oral and Intravenous Preparation
A Phase 2 study testing Rifampicin intravenous and Oral rifampicin in people with Tuberculous Meningitis, run by Universitas Padjadjaran at 1 site in Indonesia.
Trial summary
Tuberculous (TB) meningitis is the most severe manifestation of TB infection, leaving up to 50% of patients dead or neurologically disabled. Current treatment is similar to treatment of lung TB, although penetration of some antibiotics into the brain is poor and the immune-pathology of TB meningitis is very different… Read more about this study
- Who is it for?
- Ages 18 to 65 years
- Conditions the study is for
- Tuberculous Meningitis
- What is being tested?
- Rifampicin intravenous and Oral rifampicin
- Type of treatment
- Pill or oral medicine, Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 30 participants
- Where
- 1 siteIndonesia
- Study dates
- Jun 2013to Apr 2014
- 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 to 65 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Age 18 years or older
- Probable/possible tuberculosis meningitis using uniform case definition
- Agree to participate in the study
Who cannot join
- Patient with antituberculosis treatment within last 2 weeks.
- Increase liver function >5x upper limit of normal
- Pregnancy
Trial locations and contacts
1 site in 1 country.
About this study
Official title: Explorative PK Study Comparing 600 mg Rifampicin i.v. With 750 mg and 900 mg Rifampicin Oral in Tuberculous Meningitis Patients
Tuberculous (TB) meningitis is the most severe manifestation of TB infection, leaving up to 50% of patients dead or neurologically disabled. Current treatment is similar to treatment of lung TB, although penetration of some antibiotics into the brain is poor and the immune-pathology of TB meningitis is very different from pulmonary TB. In a recent phase II clinical trial from the investigators group, the first of its kind globally, intensified antibiotic treatment, with moxifloxacin and high dose rifampicin, strongly reduced mortality of TB meningitis.
The investigators aim to examine the effect of intensified antibiotic treatment on mortality and morbidity of TB meningitis in a phase 3 clinical trial, preceded with an explorative pharmacokinetic (PK) study to examine if higher oral doses rifampicin result in exposures similar to the i.v. dose used in our phase 2 trial, since oral rifampicin could be implemented much easier in low-resource settings.
Read the detailed description
Introduction:
In a recent clinical trial the investigators have shown that a higher dose of rifampicin administered intravenously (600 mg iv) during the first 2 weeks of treatment is safe and associated with a survival benefit in adults with TB meningitis. An oral (rather than iv) dose would help implementation of intensified treatment for TB meningitis. However, it is hard to predict what oral dose of rifampicin will result in rifampicin exposures similar to 600 mg iv, due to differences in bio-availability (oral vs. iv) and the unpredictable dose-concentration relationship (nonlinear pharmacokinetics of rifampicin). Therefore the investigators aim to examine the pharmacokinetic of 2 higher doses of rifampicin (750 mg and 900 mg) given orally, and compare the pharmacokinetic profiles with the result of our previous study using 600 mg rifampicin iv.
General Objective:
To help establish the optimized treatment regimen for TB meningitis
Specific Objectives:
- To explore whether exposures resulting from oral rifampicin 750 mg or 900 mg are similar to exposures after intravenous rifampicin 600 mg during the first two days of treatment
- To explore whether exposures resulting from oral rifampicin 750 mg or 900 mg are similar to exposures after 14 days of treatment (stabilized rifampicin concentrations, i..e steady-state)
- To evaluate the safety and tolerability of high dose of oral rifampicin
- To evaluate neurological response and mortality after 2 weeks of treatment with high dose rifampicin
Study Design:
Explorative pharmacokinetic study; randomized, three-arm, two-period evaluation.
Study procedure:
After diagnosis of TB meningitis, eligible patients will be randomized to get either oral 750 mg, oral 900 mg, or iv 600 mg rifampicin for 14 days in combination with standard oral TB drugs (isoniazid 300 mg/day, ethambutol 750 mg/day, and pyrazinamide 1500mg/day) and adjuvant dexamethasone i.v. and pyridoxine.
Serial blood samples will be taken 6 times from 0, 1, 2, 4, 8, and 12 hour after drug administration at the first or second day of treatment and at day 14 (steady-state). Single cerebrospinal fluid (CSF) sample will be taken 3-6 hours after administration at the same day of blood sampling days.
- Conditions
- Tuberculous Meningitis
- Being tested
- Rifampicin intravenous, Oral rifampicin
- Keywords
- tuberculous meningitis, rifampicin, bioequivalence, oral administration, intravenous administration
- Medical subject headings
- Tuberculosis, Meningeal
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Rifampicin intravenousDrug
Also called Rifadin
Oral rifampicinDrug
Also called Rifampisin (Kimia Farma, Bandung, Indonesia)
| Study group | Role | What they receive |
|---|---|---|
| Rifampicin 600 mg | Active comparator | Subjects in this arm receive 600 mg rifampicin intravenously Receives: Drug: Rifampicin intravenous |
| rifampicin 750 mg | Experimental | Subjects in this arm receive 750 mg rifampicin orally Receives: Drug: Oral rifampicin |
| rifampicin 900 mg | Experimental | Subjects in this arm receive rifampicin 900 mg orally Receives: Drug: Oral rifampicin |
What is being measured
The primary outcome is the main question the study is designed to answer.
Pharmacokinetic profile of several rifampicin dose
We will measure plasma drug concentration at hour 0, 1, 2, 4, 8, and 12, while CSF drug concentration will be measured at a single time point i.e. at hour 3-6 post dose. The sampling days will be (1) within the first three days, and (2) at day 14 of the intensified treatment.
Measured: Day 2 and Day 14; 6 time points for blood analysis, and 1 time point for CSF analysis
Secondary outcomes (1)
mortality
We will measure early and late mortality
Measured: early (1 month) and late (6 months)
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted1 Mar 2013 (estimated)
- Study startJun 2013
- Primary completionOct 2013
- Study completionApr 2014
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (2)Papers the sponsor has linked to this study.
- Other trials for Tuberculous MeningitisStudies of the same condition, open and under way.
- 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
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 30 participants (actual)
Sponsor and investigators
- Lead sponsor
- Universitas Padjadjaran
- Sponsor type
- University, hospital or other
- Collaborators
- Radboud University Medical Center
- Responsible party
- Sponsor
- Investigators
- Rovina Ruslami, M.D., PhD, Principal investigator, Faculty of Medicine Universitas Padjadjaran - Dr. Hasan Sadikin Hospital Bandung
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01802502
- Sponsor's protocol ID
- TB-201302.01
- Acronym
- REMOVER
- Status last verified
- Jun 2014
- First submitted
- 27 Feb 2013
- Last updated
- 17 Jun 2014
- Results posted
- No
- Data monitoring committee
- Yes
Publications
Ruslami R, Ganiem AR, Dian S, Apriani L, Achmad TH, van der Ven AJ, Borm G, Aarnoutse RE, van Crevel R. Intensified regimen containing rifampicin and moxifloxacin for tuberculous meningitis: an open-label, randomised controlled phase 2 trial. Lancet Infect Dis. 2013 Jan;13(1):27-35. doi: 10.1016/S1473-3099(12)70264-5. Epub 2012 Oct 25.
PubMed 23103177Marais S, Thwaites G, Schoeman JF, Torok ME, Misra UK, Prasad K, Donald PR, Wilkinson RJ, Marais BJ. Tuberculous meningitis: a uniform case definition for use in clinical research. Lancet Infect Dis. 2010 Nov;10(11):803-12. doi: 10.1016/S1473-3099(10)70138-9. Epub 2010 Sep 6.
PubMed 20822958
Study at a glance
From the registry record, last updated by the sponsor on 17 Jun 2014. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Explorative PK Study Comparing 600 mg Rifampicin i.v. With 750 mg and 900 mg Rifampicin Oral in Tuberculous Meningitis Patients
- ClinicalTrials.gov ID
- NCT01802502
- Acronym / sponsor ID
- REMOVER / TB-201302.01
- Conditions
- Tuberculous Meningitis
- Keywords
- tuberculous meningitis, rifampicin, bioequivalence, oral administration, intravenous administration
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 30 participants (actual)
- Lead sponsor
- Universitas PadjadjaranUniversity, hospital or other
- Collaborators
- Radboud University Medical Center
- Study start
- Jun 2013
- Primary completion
- Oct 2013 (actual)
- Study completion
- Apr 2014 (actual)
- First posted
- 1 Mar 2013 (estimated)
- 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.
Tuberculous (TB) meningitis is the most severe manifestation of TB infection, leaving up to 50% of patients dead or neurologically disabled. Current treatment is similar to treatment of lung TB, although penetration of some antibiotics into the brain is poor and the immune-pathology of TB meningitis is very different from pulmonary TB. In a recent phase II clinical trial from the investigators group, the first of its kind globally, intensified antibiotic treatment, with moxifloxacin and high dose rifampicin, strongly reduced mortality of TB meningitis.
The investigators aim to examine the effect of intensified antibiotic treatment on mortality and morbidity of TB meningitis in a phase 3 clinical trial, preceded with an explorative pharmacokinetic (PK) study to examine if higher oral doses rifampicin result in exposures similar to the i.v. dose used in our phase 2 trial, since oral rifampicin could be implemented much easier in low-resource settings.
Detailed description
Introduction:
In a recent clinical trial the investigators have shown that a higher dose of rifampicin administered intravenously (600 mg iv) during the first 2 weeks of treatment is safe and associated with a survival benefit in adults with TB meningitis. An oral (rather than iv) dose would help implementation of intensified treatment for TB meningitis. However, it is hard to predict what oral dose of rifampicin will result in rifampicin exposures similar to 600 mg iv, due to differences in bio-availability (oral vs. iv) and the unpredictable dose-concentration relationship (nonlinear pharmacokinetics of rifampicin). Therefore the investigators aim to examine the pharmacokinetic of 2 higher doses of rifampicin (750 mg and 900 mg) given orally, and compare the pharmacokinetic profiles with the result of our previous study using 600 mg rifampicin iv.
General Objective:
To help establish the optimized treatment regimen for TB meningitis
Specific Objectives:
- To explore whether exposures resulting from oral rifampicin 750 mg or 900 mg are similar to exposures after intravenous rifampicin 600 mg during the first two days of treatment
- To explore whether exposures resulting from oral rifampicin 750 mg or 900 mg are similar to exposures after 14 days of treatment (stabilized rifampicin concentrations, i..e steady-state)
- To evaluate the safety and tolerability of high dose of oral rifampicin
- To evaluate neurological response and mortality after 2 weeks of treatment with high dose rifampicin
Study Design:
Explorative pharmacokinetic study; randomized, three-arm, two-period evaluation.
Study procedure:
After diagnosis of TB meningitis, eligible patients will be randomized to get either oral 750 mg, oral 900 mg, or iv 600 mg rifampicin for 14 days in combination with standard oral TB drugs (isoniazid 300 mg/day, ethambutol 750 mg/day, and pyrazinamide 1500mg/day) and adjuvant dexamethasone i.v. and pyridoxine.
Serial blood samples will be taken 6 times from 0, 1, 2, 4, 8, and 12 hour after drug administration at the first or second day of treatment and at day 14 (steady-state). Single cerebrospinal fluid (CSF) sample will be taken 3-6 hours after administration at the same day of blood sampling days.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 3
| Arm | Type | Receives |
|---|---|---|
| Rifampicin 600 mg | Active comparator | Drug: Rifampicin intravenousSubjects in this arm receive 600 mg rifampicin intravenously |
| rifampicin 750 mg | Experimental | Drug: Oral rifampicinSubjects in this arm receive 750 mg rifampicin orally |
| rifampicin 900 mg | Experimental | Drug: Oral rifampicinSubjects in this arm receive rifampicin 900 mg orally |
Who may qualify
- Ages
- 18 to 65 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (3 listed)
- Age 18 years or older
- Probable/possible tuberculosis meningitis using uniform case definition
- Agree to participate in the study
Key exclusion criteria (3 listed)
- Patient with antituberculosis treatment within last 2 weeks.
- Increase liver function >5x upper limit of normal
- Pregnancy
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 |
|---|---|---|
| Rifampicin intravenousAlso: Rifadin | Drug | Rifampicin 600 mg |
| Oral rifampicinAlso: Rifampisin (Kimia Farma, Bandung, Indonesia) | Drug | rifampicin 750 mg, rifampicin 900 mg |
Primary outcome
Pharmacokinetic profile of several rifampicin dose
Time frame: Day 2 and Day 14; 6 time points for blood analysis, and 1 time point for CSF analysis
We will measure plasma drug concentration at hour 0, 1, 2, 4, 8, and 12, while CSF drug concentration will be measured at a single time point i.e. at hour 3-6 post dose. The sampling days will be (1) within the first three days, and (2) at day 14 of the intensified treatment.
1 secondary outcome
mortality
Time frame: early (1 month) and late (6 months)
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 17 Jun 2014.
- Background: PubMed 23103177Ruslami R, Ganiem AR, Dian S, Apriani L, Achmad TH, van der Ven AJ, Borm G, Aarnoutse RE, van Crevel R. Intensified regimen containing rifampicin and moxifloxacin for tuberculous meningitis: an open-label, randomised controlled phase 2 trial. Lancet Infect Dis. 2013 Jan;13(1):27-35. doi: 10.1016/S1473-3099(12)70264-5. Epub 2012 Oct 25.
- Background: PubMed 20822958Marais S, Thwaites G, Schoeman JF, Torok ME, Misra UK, Prasad K, Donald PR, Wilkinson RJ, Marais BJ. Tuberculous meningitis: a uniform case definition for use in clinical research. Lancet Infect Dis. 2010 Nov;10(11):803-12. doi: 10.1016/S1473-3099(10)70138-9. Epub 2010 Sep 6.
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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.
Rovina Ruslami, M.D., PhD principal investigator
Faculty of Medicine Universitas Padjadjaran - Dr. Hasan Sadikin Hospital Bandung
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Rifampicin intravenous and Oral rifampicin in people with Tuberculous Meningitis, run by Universitas Padjadjaran at 1 site in Indonesia.
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 3 inclusion and 3 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: finished, as of the sponsor's last update on 17 Jun 2014. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Indonesia. 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?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Pharmacokinetic profile of several rifampicin dose (time frame: Day 2 and Day 14; 6 time points for blood analysis, and 1 time point for CSF analysis). 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 NCT01802502, which also lists 2 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 17 Jun 2014.