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Project Topic
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Mortality due to Tuberculous meningitis (TBM) reaches 30% in HIV-negative and up to 70% in HIV-positive individuals with drug resistant TB strains, with death occurring most frequently in the first 2 weeks after diagnosis. Amongst TBM survivors, 50% are disabled due to neurological sequelae. Treatment of TBM has remained unchanged for decades despite this high level of mortality. INTENSE-TBM aims to improve the prognosis of TBM in patients with or without HIV co-infection in subSaharan Africa by reducing TBM mortality and neurological sequelae as well as improving the clinical management of TBM-HIV co-infection. For this purpose, INTENSE-TBM will carry out a multicentre randomised controlled trial in 4 Sub-Saharan African countries (Madagascar, Ivory Coast, Uganda and South Africa). Patients with suspected TBM will be randomised 1:1:1:1 to standard WHO TBM therapy, versus an intensified treatment (INTENSE-TBM programme), and into aspirin versus placebo therapy in a factorial design. The intensified TBM programme will consist of: i) First 5-7 days: high dose intravenous (IV) rifampicin 20 mg/kg/d, IV linezolid 1200 mg/d, IV isoniazid 5 mg/kg/d, pyrazinamide 30 mg/kg/d and corticosteroids. ii) Up until 2 month (oral): rifampicin 35 mg/kg/d, linezolid 1200 mg/d, isoniazid, pyrazinamide, and corticosteroids. iii) Seven months: isoniazid 5 mg/kg/d and rifampicin 10 mg/kg/d Patients will also be randomised to receive either aspirin 150 mg per day or placebo for the first two months of treatment. If superiority of this experimental arm is demonstrated in terms of reduced mortality, INTENSE-TBM will become the first Phase III study to demonstrate survival benefit from intensified TBM treatment. HIV co-infected patients will start a generic formulation of tenofovir, lamivudine, and dolutegravir four weeks after TBM treatment initiation, and continue with dexamethasone for at least the first four weeks of antiretroviral treatment. Incidence and risk-factors for severe immune reconstitution inflammatory syndrome will be determined and the pharmacokinetics of the drug-drug interactions between standard and high dose rifampicin with dolutegravir analysed. INTENSE-TBM responds directly to the call by evaluating (i) the impact of an optimized drug regimen for TBM on mortality including high dose rifampicin and linezolid, a repurposed drug for the treatment of TBM, (ii) the impact of the addition of aspirin on TBM mortality, a drug that has not previously been authorised for use against any infectious disease (iii) an antiretroviral therapy strategy in TBM patient co-infected with HIV to specifically assess the risk of severe IRIS, and to study drug-drug interactions.
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