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Trial record 3 of 10 for:    DIAN

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

This study is not yet open for participant recruitment. (see Contacts and Locations)
Verified June 2014 by Universitas Padjadjaran
Sponsor:
Collaborators:
United States Agency for International Development (USAID)
Radboud University
Information provided by (Responsible Party):
Universitas Padjadjaran
ClinicalTrials.gov Identifier:
NCT02169882
First received: June 15, 2014
Last updated: June 20, 2014
Last verified: June 2014
  Purpose

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 Intervention Phase
Tuberculosis, Meningeal
Drug: Placebo
Drug: Rifampicin
Drug: Other TB drugs
Drug: Adjuvant dexamethasone
Phase 2
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Pharmacokinetics Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, 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

Resource links provided by NLM:


Further study details as provided by Universitas Padjadjaran:

Primary Outcome Measures:
  • Rifampicin concentrations in plasma and cerebrospinal fluid (CSF) [ Time Frame: Day 2 (+/- 1) after administration of study drugs ] [ Designated as safety issue: Yes ]
    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:
  • Rifampicin concentrations in plasma and CSF at steady-state [ Time Frame: Day 10 (+/- 1) after starting treatment with study drugs ] [ Designated as safety issue: Yes ]
    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.

  • Grade 3 and 4 and serious adverse events [ Time Frame: Within 60 days ] [ Designated as safety issue: Yes ]
    Determined by measurement of liver function, hematology, gastrointestinal intolerance and hypersensitivity at days 3, 7, 10, 14, 30, 45, and 60

  • Mortality [ Time Frame: 180 days ] [ Designated as safety issue: No ]
  • Neurological response [ Time Frame: Within 60 days ] [ Designated as safety issue: No ]
    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.

  • Neuroradiological response [ Time Frame: 60 days ] [ Designated as safety issue: No ]
    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

  • Resolution of blood and CSF inflammatory response [ Time Frame: 7 days ] [ Designated as safety issue: No ]
    Inflammatory response will be measured at day 0 and day 7

  • Sensitivity of GeneXpert for diagnosing TBM [ Time Frame: Within 6 weeks ] [ Designated as safety issue: No ]
    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.


Estimated Enrollment: 60
Study Start Date: July 2014
Estimated Study Completion Date: December 2016
Estimated Primary Completion Date: June 2016 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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)

  Eligibility

Ages Eligible for Study:   15 Years and older
Genders Eligible for Study:   Both
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
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT02169882

Contacts
Contact: Ahmad R Ganiem, M.D., PhD +62 878 2288 3773 rizalbdg@gmail.com
Contact: Sofiati Dian, M.D. +62 812 2119 519 sofiatidian@gmail.com

Locations
Indonesia
Hasan Sadikin General Hospital Not yet recruiting
Bandung, Jawa Barat, Indonesia, 40161
Sub-Investigator: Ahmad R Ganiem, M.D., PhD         
Sub-Investigator: Sofiati Dian, M.D.         
Sub-Investigator: Vycke Yunivita, M.D.         
Sponsors and Collaborators
Universitas Padjadjaran
United States Agency for International Development (USAID)
Radboud University
Investigators
Principal Investigator: Rovina Ruslami, M.D., PhD Faculty of Medicine Universitas Padjadjaran, Bandung, Indonesia
  More Information

Publications:
Responsible Party: Universitas Padjadjaran
ClinicalTrials.gov Identifier: NCT02169882     History of Changes
Other Study ID Numbers: TB-201406.01, PGA-2000003601
Study First Received: June 15, 2014
Last Updated: June 20, 2014
Health Authority: Indonesia: Ministry of Health

Keywords provided by Universitas Padjadjaran:
Tuberculous meningitis
Rifampicin
Dose finding study
Pharmacokinetics

Additional relevant MeSH terms:
Meningitis
Tuberculosis
Tuberculosis, Meningeal
Actinomycetales Infections
Bacterial Infections
Central Nervous System Bacterial Infections
Central Nervous System Diseases
Central Nervous System Infections
Gram-Positive Bacterial Infections
Meningitis, Bacterial
Mycobacterium Infections
Nervous System Diseases
Tuberculosis, Central Nervous System
BB 1101
Dexamethasone
Dexamethasone 21-phosphate
Dexamethasone acetate
Rifampin
Anti-Bacterial Agents
Anti-Infective Agents
Anti-Inflammatory Agents
Antibiotics, Antitubercular
Antiemetics
Antineoplastic Agents
Antineoplastic Agents, Hormonal
Antitubercular Agents
Autonomic Agents
Central Nervous System Agents
Enzyme Inhibitors
Gastrointestinal Agents

ClinicalTrials.gov processed this record on November 23, 2014