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Immediate Versus Deferred Antiretroviral Therapy for HIV-Associated Tuberculous Meningitis

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ClinicalTrials.gov Identifier: NCT00433719
Recruitment Status : Unknown
Verified June 2008 by University of Oxford.
Recruitment status was:  Active, not recruiting
First Posted : February 12, 2007
Last Update Posted : August 7, 2008
Sponsor:
Collaborator:
Information provided by:

Study Description
Brief Summary:
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 or disease Intervention/treatment
HIV Infections Tuberculous Meningitis Drug: Combivir and efavirenz

Detailed Description:

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.


Study Design

Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 253 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Randomised Controlled Trial of Immediate Versus Deferred Antiretroviral Therapy for HIV-Associated Tuberculous Meningitis
Study Start Date : September 2005
Estimated Primary Completion Date : December 2008
Estimated Study Completion Date : December 2008


Arms and Interventions

Arm Intervention/treatment
Experimental: 1
Combivir, efavirenz for 12 months
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
Placebo Comparator: 2
Placebo for 2 months followed by Combivir and efavirenz for 10 months
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


Outcome Measures

Primary Outcome Measures :
  1. Mortality [ Time Frame: 9 months ]

Secondary Outcome Measures :
  1. Mortality [ Time Frame: 12 months ]
  2. Fever clearance time
  3. Coma clearance time
  4. CD4 count [ Time Frame: 12 months ]
  5. plasma HIV RNA [ Time Frame: 12 months ]
  6. Grade 3 or 4 adverse event [ Time Frame: Any ]
  7. Neurological disability [ Time Frame: 12 months ]

Eligibility Criteria

Information from the National Library of Medicine

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

Inclusion Criteria:

  • age 15 years or older
  • HIV antibody positive
  • clinical diagnosis of TB meningitis

Exclusion Criteria:

  • positive CSF Gram or India ink stain
  • known or suspected pregnancy
  • antituberculous treatment 8 - 30 days immediately prior to recruitment
  • previous antiretroviral therapy
  • laboratory contraindications to antiretroviral or antituberculous therapy
  • lack of consent.
Contacts and Locations

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00433719


Locations
Vietnam
Hospital for Tropical Diseases
Ho Chi Minh City, Vietnam
Pham Ngoc Thach Hospital
Ho Chi Minh City, Vietnam
Sponsors and Collaborators
University of Oxford
Wellcome Trust
Investigators
Principal Investigator: Estee Torok University of Oxford
More Information

Responsible Party: Centre for Tropical Diseases, University of Oxford
ClinicalTrials.gov Identifier: NCT00433719     History of Changes
Other Study ID Numbers: OXTREC 023-04
ISRCTN63659091
First Posted: February 12, 2007    Key Record Dates
Last Update Posted: August 7, 2008
Last Verified: June 2008

Keywords provided by University of Oxford:
Human immunodeficiency virus
Tuberculous meningitis
Treatment Naive

Additional relevant MeSH terms:
HIV Infections
Meningitis
Tuberculosis
Tuberculosis, Meningeal
Lentivirus Infections
Retroviridae Infections
RNA Virus Infections
Virus Diseases
Sexually Transmitted Diseases, Viral
Sexually Transmitted Diseases
Immunologic Deficiency Syndromes
Immune System Diseases
Central Nervous System Diseases
Nervous System Diseases
Mycobacterium Infections
Actinomycetales Infections
Gram-Positive Bacterial Infections
Bacterial Infections
Meningitis, Bacterial
Central Nervous System Bacterial Infections
Tuberculosis, Central Nervous System
Central Nervous System Infections
Efavirenz
Lamivudine, zidovudine drug combination
Reverse Transcriptase Inhibitors
Nucleic Acid Synthesis Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Anti-Retroviral Agents
Antiviral Agents