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

• Sponsor: Universitas Padjadjaran
• Collaborators: United States Agency for International Development (USAID); Radboud University
• Information provided by (Responsible Party): Universitas Padjadjaran

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Tuberculosis, Meningeal	Drug: Placebo; Drug: Rifampicin; Drug: Other TB drugs; Drug: Adjuvant dexamethasone	Phase 2; Phase 3

Study Design

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Study Type :	Interventional (Clinical Trial)
Actual Enrollment :	60 participants
Allocation:	Randomized
Intervention Model:	Parallel Assignment
Masking:	Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose:	Treatment
Official Title:	A Randomized Double Blinded Phase 2b Clinical Trial Comparing Standard Dose With Two Higher Doses of Rifampicin for Treatment of Adults With Tuberculous Meningitis
Actual Study Start Date :	December 1, 2014
Actual Primary Completion Date :	November 5, 2016
Actual Study Completion Date :	May 5, 2017

Arms and Interventions

Arm	Intervention/treatment
Active Comparator: 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)	Drug: 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.; 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); Drug: Adjuvant dexamethasone; Patients will receive dexamethasone in decreasing dose (in 6-8 weeks, according to TBM severity grade on admission)
Experimental: 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)	Drug: 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.; 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.; Other Name: Rifampisin - Kimia Farma; 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); Drug: Adjuvant dexamethasone; Patients will receive dexamethasone in decreasing dose (in 6-8 weeks, according to TBM severity grade on admission)
Experimental: 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)	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.; Other Name: Rifampisin - Kimia Farma; 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); Drug: Adjuvant dexamethasone; Patients will receive dexamethasone in decreasing dose (in 6-8 weeks, according to TBM severity grade on admission)

Outcome Measures

Primary Outcome Measures :

1. Rifampicin concentrations in plasma and cerebrospinal fluid (CSF) [ Time Frame: Day 2 (+/- 1) after administration of study drugs ]
   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.

Secondary Outcome Measures :

1. Rifampicin concentrations in plasma and CSF at steady-state [ Time Frame: Day 10 (+/- 1) after starting treatment with study drugs ]
   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.
2. Grade 3 and 4 and serious adverse events [ Time Frame: Within 60 days ]
   Determined by measurement of liver function, hematology, gastrointestinal intolerance and hypersensitivity at days 3, 7, 10, 14, 30, 45, and 60
3. Mortality [ Time Frame: 180 days ]
4. Neurological response [ Time Frame: Within 60 days ]
   Neurological responses that show both improvement (e.g. time to resolution of comma, time to fever resolution) and worsening (time to development of neurological deficits) will be measured and recorded at days 3, 7, 30 and 60.
5. Neuroradiological response [ Time Frame: 60 days ]
   Development of infarction or other complication of TBM will documented by performing and comparing brain MRIs that will be done within the first 5 day and 60 day (+/- 5 days) after randomization
6. Resolution of blood and CSF inflammatory response [ Time Frame: 7 days ]
   Inflammatory response will be measured at day 0 and day 7
7. Sensitivity of GeneXpert for diagnosing TBM [ Time Frame: Within 6 weeks ]
   Every CSF sample from patients who come with suspicion of TBM will be inoculated in GeneXpert cartridge and standard culture measures (MODS), and the result will be compared.

Eligibility Criteria

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Ages Eligible for Study:	15 Years and older (Child, Adult, Older Adult)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

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)

Contacts and Locations

Locations

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Indonesia
Hasan Sadikin General Hospital
Bandung, Jawa Barat, Indonesia, 40161

Sponsors and Collaborators

Universitas Padjadjaran

United States Agency for International Development (USAID)

Radboud University

Investigators

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Principal Investigator:	Rovina Ruslami, M.D., PhD	Faculty of Medicine Universitas Padjadjaran, Bandung, Indonesia

More Information

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.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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). pii: e01014-18. doi: 10.1128/AAC.01014-18. Print 2018 Dec.

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Responsible Party:	Universitas Padjadjaran
ClinicalTrials.gov Identifier:	NCT02169882 History of Changes
Other Study ID Numbers:	TB-201406.01; PGA-2000003601 ( Other Identifier: PEER Health )
First Posted:	June 23, 2014
Last Update Posted:	June 1, 2017
Last Verified:	December 2016
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD:	No

Keywords provided by Universitas Padjadjaran:

Tuberculous meningitis; Rifampicin; Dose finding study; Pharmacokinetics

Additional relevant MeSH terms:

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Tuberculosis; Meningitis; Tuberculosis, Meningeal; Mycobacterium Infections; Actinomycetales Infections; Gram-Positive Bacterial Infections; Bacterial Infections; Central Nervous System Diseases; Nervous System Diseases; Meningitis, Bacterial; Central Nervous System Bacterial Infections; Tuberculosis, Central Nervous System; Central Nervous System Infections; Dexamethasone; Dexamethasone acetate	BB 1101; Rifampin; Pyrazinamide; Ethambutol; Pyridoxine; Anti-Inflammatory Agents; Antiemetics; Autonomic Agents; Peripheral Nervous System Agents; Physiological Effects of Drugs; Gastrointestinal Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal