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Sponsors and Collaborators: |
University of Oxford Wellcome Trust |
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Information provided by: | University of Oxford |
ClinicalTrials.gov Identifier: | NCT00433719 |
The optimal time to initiate antiretroviral therapy (ART) in HIV-associated tuberculous meningitis (TBM) unknown. There are concerns that immediate ART may worsen rather than improve outcome, because drug interactiond and toxicities or development of an intracerebral immune reconstitution inflammatory syndrome (IRIS). Conversely, delaying ART may result in increased HIV-related deaths. To answer this question, we are conducting a randomised, double-blind placebo-controlled trial comparing immediate and deferred ART in HIV-infected patients presenting with TBM, to assess effect on survival.
Condition | Intervention |
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HIV Infections Tuberculous Meningitis |
Drug: Combivir and efavirenz |
Study Type: | Interventional |
Study Design: | Treatment, Randomized, Double Blind (Subject, Investigator, Outcomes Assessor), Placebo Control, Parallel Assignment, Safety/Efficacy Study |
Official Title: | Randomised Controlled Trial of Immediate Versus Deferred Antiretroviral Therapy for HIV-Associated Tuberculous Meningitis |
Enrollment: | 253 |
Study Start Date: | September 2005 |
Estimated Study Completion Date: | December 2008 |
Estimated Primary Completion Date: | December 2008 (Final data collection date for primary outcome measure) |
Arms | Assigned Interventions |
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1: Experimental
Combivir, efavirenz for 12 months
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Drug: Combivir and efavirenz
Arm 1: Combivir and efavirenz for 12 months Arm 2: Placebo for 2 months then Combivir and efavirenz for 10 months
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2: Placebo Comparator
Placebo for 2 months followed by Combivir and efavirenz for 10 months
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Drug: Combivir and efavirenz
Arm 1: Combivir and efavirenz for 12 months Arm 2: Placebo for 2 months then Combivir and efavirenz for 10 months
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Title: Study of immediate versus deferred antiretroviral therapy in HIV-associated tuberculous meningitis Study design: A randomized, double blind, placebo-controlled trial with 2 parallel arms Sample size: 247 Inclusion criteria: Age 15 years or older; HIV antibody positive; clinical diagnosis of TBM.
Exclusion criteria: positive CSF Gram or India ink stain, known or suspected pregnancy; antituberculous treatment 8 to 30 days immediately prior to recruitment; previous antiretroviral therapy; laboratory contraindications to antiretroviral or antituberculous therapy; lack of consent.
Consent: Written informed consent will be sought for all patients. Verbal consent will be considered acceptable when written consent is impossible. In unconscious patients, the consent of 2 independent physicians will be considered acceptable.
Randomization: Patients will be stratified according to TBM disease severity at presentation (modified MRC grade I to III). Within each stratum, patients will be randomized to 1 of the 2 treatment arms: immediate or deferred (2 months) ART.
Antituberculous treatment: Initial therapy will be with isonazid, rifampicin, pyrazinamide and ethambutol for 3 months. After 3 months, patients will continue on rifampicin and isoniazid for a further 6 months.
Corticosteroid treatment: Dexamethasone 0.3 - 0.4mg/kg will be administered and tapered over 6 - 8 weeks, according to TBM grade.
Antiretrovira l treatment: Antiretrovirals (zidovudine, lamivudine and efavirenz)or identical placebo tablets will be commenced at study entry and continued for 2 months. Thereafter, all patients will received antiretrovirals.
Clinical monitoring: Patients will be assessed weekly as an inpatient for 3 months. Hospital outpatient review will occur monthly until 9 months. A final follow-up visit will take place at 12 months.
Laboratory monitoring: Routine laboratory tests will be monitored weekly as an inpatient and monthly as an outpatient. Blood samples for CD4 T-lymphocyte count and plasma HIV-1 RNA level will be monitored 3-monthly. CSF samples will be taken at 0, 1, 2, 3, 6 and 9 months.
Radiology: Patients will have a chest radiograph performed on admission. A CT or MRI brain scan may also be performed if clinically indicated.
Adverse events: All grade 3 and 4 adverse events will be reported immediately to the Data and Safety Monitoring Committee.
Outcome measures: The primary endpoint will be mortality at 9 months. The secondary endpoints will be: mortality at 12 months; fever clearance time; coma clearance time; neurological relapse; progression to new or recurrent AIDS defining illness; any grade 3 or 4 adverse event; CD4 count response; plasma HIV-1 RNA response; neurological disability.
Data analysis: Analysis will be based on intention to treat.
Ages Eligible for Study: | 15 Years and older |
Genders Eligible for Study: | Both |
Accepts Healthy Volunteers: | No |
Inclusion Criteria:
Exclusion Criteria:
Vietnam | |
Hospital for Tropical Diseases | |
Ho Chi Minh City, Vietnam | |
Pham Ngoc Thach Hospital | |
Ho Chi Minh City, Vietnam |
Principal Investigator: | Estee Torok | University of Oxford |
Responsible Party: | University of Oxford ( Centre for Tropical Diseases ) |
Study ID Numbers: | OXTREC 023-04, ISRCTN63659091 |
Study First Received: | January 25, 2007 |
Last Updated: | August 6, 2008 |
ClinicalTrials.gov Identifier: | NCT00433719 |
Health Authority: | United Kingdom: Research Ethics Committee; Vietnam: Ho Chi Minh City Health Service |
Human immunodeficiency virus Tuberculous meningitis Treatment Naive |
Bacterial Infections Efavirenz Sexually Transmitted Diseases, Viral Meningitis, Bacterial Acquired Immunodeficiency Syndrome Tuberculous meningitis Central Nervous System Diseases Tuberculosis, Meningeal Immunologic Deficiency Syndromes |
Meningitis Virus Diseases Gram-Positive Bacterial Infections Central Nervous System Infections HIV Infections Sexually Transmitted Diseases Mycobacterium Infections Tuberculosis Retroviridae Infections |
Anti-Infective Agents RNA Virus Infections Anti-HIV Agents Slow Virus Diseases Immune System Diseases Molecular Mechanisms of Pharmacological Action Nervous System Diseases Enzyme Inhibitors Infection Antiviral Agents |
Pharmacologic Actions Actinomycetales Infections Reverse Transcriptase Inhibitors Anti-Retroviral Agents Therapeutic Uses Tuberculosis, Central Nervous System Lentivirus Infections Central Nervous System Bacterial Infections Nucleic Acid Synthesis Inhibitors |