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

NCT02169882 | Completed Phase 2 DMC

• 2 other identifiers: TB-201406.01PGA-2000003601
• Study Type: interventional
• Target: 60
• Locations: 1 country
• Sites: 1

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

Conditions

Tuberculosis, Meningeal

Keywords

Tuberculous meningitis; Rifampicin; Dose finding study; Pharmacokinetics

Outcome Measures

Primary Outcomes (1)

• Rifampicin concentrations in plasma and cerebrospinal fluid (CSF)

  The rifampicin concentrations in plasma are measured from blood samples that are obtained by intensive pharmacokinetic sampling at 6 sampling time points (h0, 1, 2, 4, 8, 12 post dose). CSF rifampicin concentration will be measured using CSF sample taken by means of lumbar puncture at hour 3-6 post dose at the same day of blood sampling.

  Day 2 (+/- 1) after administration of study drugs

Secondary Outcomes (7)

• Rifampicin concentrations in plasma and CSF at steady-state

  Day 10 (+/- 1) after starting treatment with study drugs

• Grade 3 and 4 and serious adverse events

  Within 60 days

• Mortality

  180 days

• Neurological response

  Within 60 days

• Neuroradiological response

  60 days

Study Arms (3)

Rifampicin 450 mg (standard dose)

ACTIVE COMPARATOR

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)

Drug: Placebo; Drug: Other TB drugs; Drug: Adjuvant dexamethasone

Rifampicin 900 mg per oral

EXPERIMENTAL

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)

Drug: Placebo; Drug: Rifampicin; Drug: Other TB drugs; Drug: Adjuvant dexamethasone

Rifampicin 1350 mg per oral

EXPERIMENTAL

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)

Drug: Rifampicin; Drug: Other TB drugs; Drug: Adjuvant dexamethasone

Interventions

Placebo 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 450 mg (standard dose); Rifampicin 900 mg per oral

Rifampicin 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.

Also known as: Rifampisin - Kimia Farma

Rifampicin 1350 mg per oral; Rifampicin 900 mg per oral

Other TB drugs 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)

Rifampicin 1350 mg per oral; Rifampicin 450 mg (standard dose); Rifampicin 900 mg per oral

Adjuvant dexamethasone DRUG

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

Rifampicin 1350 mg per oral; Rifampicin 450 mg (standard dose); Rifampicin 900 mg per oral

Eligibility Criteria

• Age: 15 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• Male or Female, aged 15 years or above.
• Clinical suspicion of TBM and CSF/blood glucose ratio \< 0.5.
• None or less than 3 days of anti-tuberculosis chemotherapy taken for the current infection.
• Patient or representative (if the patient is incapacitated) is willing and able to give informed consent for participation in the study.
• Willingness to allow storage of specimens.

You may not qualify if:

• Patients may not enter the study if any of the following apply:
• Liver dysfunction (ALT \> 5 times upper limit); kidney dysfunction (eGFR \< 50 ml/min)
• Pregnancy or breastfeeding (negative urine pregnancy test for all females of child-bearing age).
• Confirmed cryptococcus meningitis (LFA), or confirmed bacterial meningitis (microscopy).
• Rapid clinical deterioration at time of presentation (e.g. signs of sepsis, decreasing consciousness or signs of cerebral oedema, or herniation)

Sponsors & Collaborators

• Universitas Padjadjaran: lead
• United States Agency for International Development (USAID): collaborator
• Radboud University Medical Center: collaborator

Study Sites (1)

Hasan Sadikin General Hospital

Bandung, West Java, 40161, Indonesia

Location

Related Publications (2)

• 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.

  PMID: 23103177 BACKGROUND

• 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.

  PMID: 30224533 DERIVED

MeSH Terms

Conditions

Tuberculosis, Meningeal

Interventions

Rifampin

Condition Hierarchy (Ancestors)

Meningitis, Bacterial; Central Nervous System Bacterial Infections; Bacterial Infections; Bacterial Infections and Mycoses; Infections; Tuberculosis, Central Nervous System; Tuberculosis, Extrapulmonary; Tuberculosis; Mycobacterium Infections; Actinomycetales Infections; Gram-Positive Bacterial Infections; Central Nervous System Infections; Central Nervous System Diseases; Nervous System Diseases; Meningitis; Neuroinflammatory Diseases

Intervention Hierarchy (Ancestors)

Rifamycins; Heterocyclic Compounds, 4 or More Rings; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Lactams, Macrocyclic; Macrocyclic Compounds; Polycyclic Compounds

Study Officials

• Rovina Ruslami, M.D., PhD

  Faculty of Medicine Universitas Padjadjaran, Bandung, Indonesia

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: June 15, 2014
• First Posted: June 23, 2014
• Study Start: December 1, 2014
• Primary Completion: November 5, 2016
• Study Completion: May 5, 2017
• Last Updated: June 1, 2017

Record last verified: 2016-12

Data Sharing

• IPD Sharing: Will not share

Locations

ID (1)