Immediate Versus Deferred Antiretroviral Therapy for HIV-Associated Tuberculous Meningitis

HIV Infections Clinical Trial

Official title:

Randomised Controlled Trial of Immediate Versus Deferred Antiretroviral Therapy for HIV-Associated Tuberculous Meningitis

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT00433719
• Other study ID #: OXTREC 023-04
• Secondary ID: ISRCTN63659091
• Status: Active, not recruiting
• Phase: N/A
• First received: January 25, 2007
• Last updated: August 6, 2008
• Start date: September 2005
• Est. completion date: December 2008

Study information

• Verified date: June 2008
• Source: University of Oxford
• Contact: n/a
• Is FDA regulated: No
• Health authority: United Kingdom: Research Ethics CommitteeVietnam: Ho Chi Minh City Health Service
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 253
• Est. completion date: December 2008
• Est. primary completion date: December 2008
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 15 Years and older

Eligibility

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.

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Investigator, Outcomes Assessor), Primary Purpose: Treatment

Related Conditions & MeSH terms

• HIV Infections
• Meningitis
• Tuberculosis
• Tuberculosis, Meningeal
• Tuberculous Meningitis

Intervention

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

Locations

Country	Name	City	State
Vietnam	Hospital for Tropical Diseases	Ho Chi Minh City
Vietnam	Pham Ngoc Thach Hospital	Ho Chi Minh City

Sponsors (2)

Lead Sponsor	Collaborator
University of Oxford	Wellcome Trust

Country where clinical trial is conducted

Vietnam, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Mortality		9 months	No
Secondary	Mortality		12 months	No
Secondary	Fever clearance time			No
Secondary	Coma clearance time			No
Secondary	CD4 count		12 months	No
Secondary	plasma HIV RNA		12 months	No
Secondary	Grade 3 or 4 adverse event		Any	Yes
Secondary	Neurological disability		12 months	No