High-dose Rifampicin for the Treatment of Tuberculous Meningitis: a Dose-finding Study

NCT ID: NCT02169882

Last Updated: 2017-06-01

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2/PHASE3
• Total Enrollment: 60 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2014-12-01
• Study Completion Date: 2017-05-05

Brief Summary

Tuberculous meningitis (TBM) is the most severe form of tuberculosis infection with high mortality. Current treatment regimens are not based on clinical trials. Rifampicin is a key drug for TBM, but its penetration into the brain is limited, suggesting that a higher dose may be more effective.

There are several highly relevant, outstanding questions related to the appropriate dose of rifampicin for TBM, before a multicenter phase 3 trial can be performed. These are:

1. Previous phase 2a randomized clinical trial (done in the same setting as this proposed study) suggests that high doses of intravenous rifampicin (600mg, circa 13 mg/mg) for TBM is safe and associated with a survival benefit in adults. Given that i.v. rifampicin is not readily available, this needs to be confirmed using an equivalent higher oral dose of rifampicin.

2. Recent pharmacokinetic analysis of a continuation trial comparing 600 mg i.v. rifampicin with 750 mg and 900 mg oral rifampicin suggests that an even higher dose may be needed; but this has not been examined

3. Based on those previous data, there is a need to explore a longer duration of high-dose rifampicin for a subsequent phase 3 randomized clinical trial; treatment response in the investigators previous trial suggest that the optimal duration may be > 14 days.

4. There is a need to explore relevant treatment endpoints besides mortality including neurological, neuroradiological and inflammatory response.

Conditions

Tuberculosis, Meningeal

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

Rifampicin 450 mg (standard dose)

Twenty patients will receive 1 tablet of 450 mg Rifampicin and 2 tablets of placebo once daily for 30 days.

Unconscious subjects will receive oral drugs via nasogastric tubes (NGT).

After completion of one-month treatment, patients will receive 1 tablet of 450 mg Rifampicin.

Along with study drug and placebo, patients will receive other oral TB drugs (INH, Ethambutol, and Pyrazinamide) and pyridoxin, in accordance to National TB Program guidelines for 6 months.

Patients will also receive dexamethasone in decreasing dose (in 6-8 weeks, according to TBM severity grade on admission)

Group Type: ACTIVE_COMPARATOR

Placebo

Intervention Type: DRUG

Patients receiving 450 mg rifampicin will receive additional 2 placebo tablets, while those who receive 900 mg rifampicin will receive 1 placebo tablet.

Patients receiving 1350 mg rifampicin will not receive any placebo tablet.

With this arrangement, every subject will receive 3 tablets of study drugs.

Other TB drugs

Intervention Type: DRUG

Along with study drug and placebo, patients will receive other oral TB drugs (INH, Ethambutol, and Pyrazinamide) and pyridoxin, in accordance to National TB Program guidelines for 6 months.

Unconscious subjects will receive oral drugs via nasogastric tubes (NGT)

Adjuvant dexamethasone

Intervention Type: DRUG

Patients will receive dexamethasone in decreasing dose (in 6-8 weeks, according to TBM severity grade on admission)

Rifampicin 900 mg per oral

Twenty patients will receive 2 tablets of 450 mg Rifampicin and 1 tablet of placebo once daily for 30 days.

Unconscious subjects will receive oral drugs via nasogastric tubes (NGT)

After completion of one-month treatment, patients will receive 1 tablet of 450 mg Rifampicin.

Along with study drug and placebo, patients will receive other oral TB drugs (INH, Ethambutol, and Pyrazinamide) and pyridoxin, in accordance to National TB Program guidelines for 6 months.

Patients will also receive dexamethasone in decreasing dose (in 6-8 weeks, according to TBM severity grade on admission)

Group Type: EXPERIMENTAL

Placebo

Intervention Type: DRUG

Patients receiving 450 mg rifampicin will receive additional 2 placebo tablets, while those who receive 900 mg rifampicin will receive 1 placebo tablet.

Patients receiving 1350 mg rifampicin will not receive any placebo tablet.

With this arrangement, every subject will receive 3 tablets of study drugs.

Rifampicin

Intervention Type: DRUG

Patients in experimental arms will receive either 1 or 2 additional tablets of rifampicin.

Placebo tablets will be added accordingly, so that every study subject will receive 3 tablets of rifampicin plus placebo as described in the Arms section.

Other TB drugs

Intervention Type: DRUG

Along with study drug and placebo, patients will receive other oral TB drugs (INH, Ethambutol, and Pyrazinamide) and pyridoxin, in accordance to National TB Program guidelines for 6 months.

Unconscious subjects will receive oral drugs via nasogastric tubes (NGT)

Adjuvant dexamethasone

Intervention Type: DRUG

Patients will receive dexamethasone in decreasing dose (in 6-8 weeks, according to TBM severity grade on admission)

Rifampicin 1350 mg per oral

Twenty patients will receive 3 tablets of 450 mg Rifampicin and 0 tablet of placebo once daily for 30 days.

Unconscious subjects will receive oral drugs via nasogastric tubes (NGT)

After completion of one-month treatment, patients will receive 1 tablet of 450 mg Rifampicin.

Along with study drug and placebo, patients will receive other oral TB drugs (INH, Ethambutol, and Pyrazinamide) and pyridoxin, in accordance to National TB Program guidelines for 6 months.

Patients will also receive dexamethasone in decreasing dose (in 6-8 weeks, according to TBM severity grade on admission)

Group Type: EXPERIMENTAL

Rifampicin

Intervention Type: DRUG

Patients in experimental arms will receive either 1 or 2 additional tablets of rifampicin.

Placebo tablets will be added accordingly, so that every study subject will receive 3 tablets of rifampicin plus placebo as described in the Arms section.

Other TB drugs

Intervention Type: DRUG

Along with study drug and placebo, patients will receive other oral TB drugs (INH, Ethambutol, and Pyrazinamide) and pyridoxin, in accordance to National TB Program guidelines for 6 months.

Unconscious subjects will receive oral drugs via nasogastric tubes (NGT)

Adjuvant dexamethasone

Intervention Type: DRUG

Patients will receive dexamethasone in decreasing dose (in 6-8 weeks, according to TBM severity grade on admission)

Interventions

Placebo

Patients receiving 450 mg rifampicin will receive additional 2 placebo tablets, while those who receive 900 mg rifampicin will receive 1 placebo tablet.

Patients receiving 1350 mg rifampicin will not receive any placebo tablet.

With this arrangement, every subject will receive 3 tablets of study drugs.

Intervention Type: DRUG

Rifampicin

Patients in experimental arms will receive either 1 or 2 additional tablets of rifampicin.

Placebo tablets will be added accordingly, so that every study subject will receive 3 tablets of rifampicin plus placebo as described in the Arms section.

Intervention Type: DRUG

Other TB drugs

Along with study drug and placebo, patients will receive other oral TB drugs (INH, Ethambutol, and Pyrazinamide) and pyridoxin, in accordance to National TB Program guidelines for 6 months.

Unconscious subjects will receive oral drugs via nasogastric tubes (NGT)

Intervention Type: DRUG

Adjuvant dexamethasone

Patients will receive dexamethasone in decreasing dose (in 6-8 weeks, according to TBM severity grade on admission)

Intervention Type: DRUG

Other Intervention Names

Rifampisin - Kimia Farma

Eligibility Criteria

Inclusion Criteria

1. Male or Female, aged 15 years or above.

2. Clinical suspicion of TBM and CSF/blood glucose ratio < 0.5.

3. None or less than 3 days of anti-tuberculosis chemotherapy taken for the current infection.

4. Patient or representative (if the patient is incapacitated) is willing and able to give informed consent for participation in the study.

5. Willingness to allow storage of specimens.

Exclusion Criteria

Patients may not enter the study if any of the following apply:

1. Liver dysfunction (ALT > 5 times upper limit); kidney dysfunction (eGFR < 50 ml/min)

2. Pregnancy or breastfeeding (negative urine pregnancy test for all females of child-bearing age).

3. Confirmed cryptococcus meningitis (LFA), or confirmed bacterial meningitis (microscopy).

4. Rapid clinical deterioration at time of presentation (e.g. signs of sepsis, decreasing consciousness or signs of cerebral oedema, or herniation)

• Minimum Eligible Age: 15 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

United States Agency for International Development (USAID)

FED

Sponsor Role: collaborator

Radboud University Medical Center

OTHER

Sponsor Role: collaborator

Universitas Padjadjaran

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Rovina Ruslami, M.D., PhD

Role: PRINCIPAL_INVESTIGATOR

Faculty of Medicine Universitas Padjadjaran, Bandung, Indonesia

Locations

Hasan Sadikin General Hospital

Bandung, West Java, Indonesia

Countries

Indonesia

References

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.

Reference Type: BACKGROUND

PMID: 23103177 (View on PubMed)

Dian S, Yunivita V, Ganiem AR, Pramaesya T, Chaidir L, Wahyudi K, Achmad TH, Colbers A, Te Brake L, van Crevel R, Ruslami R, Aarnoutse R. Double-Blind, Randomized, Placebo-Controlled Phase II Dose-Finding Study To Evaluate High-Dose Rifampin for Tuberculous Meningitis. Antimicrob Agents Chemother. 2018 Nov 26;62(12):e01014-18. doi: 10.1128/AAC.01014-18. Print 2018 Dec.

Reference Type: DERIVED

PMID: 30224533 (View on PubMed)

Other Identifiers

PGA-2000003601

Identifier Type: OTHER

Identifier Source: secondary_id

TB-201406.01

Identifier Type: -

Identifier Source: org_study_id