Cryptococcal meningitis (CM) is one of the key drivers of global HIVmortalityand it must be addressed if Sustainable Development Goals are to be achieved. Significant advances in the management of CM have taken place over recent years, however substantial challenges remain for deployment and scale-up. In particular,flucytosine (5FC) is a key component of the new WHO recommended gold standard treatment, however its implementation continues to be plagued in part by unavailability and poorly adapted existing formulations requiring four times daily dosing. This proposal tackles two of the most pressing issues surrounding 5FC in LMICs by: 1) Addressing the unavailability of standard formulations of 5FC; and 2) Developing a new,easy to administer formulation of 5FC in lieu of the current standard 5FC formulation that needs to be given four times daily at the current recommended dosage of 100mg/kg/day.Work planned in this proposal includes all the necessary studies to allow submission of the new improved formulation to WHO prequalification and registration in selected Africancountries. The Phase I programme will consist of two clinical studies evaluating the comparative bioavailability of the modified release (MR) formulation against standard 5FC conducted under fasted and fed conditions, and comparative assessment at steady-state. After decision-gate, a Phase II study will evaluate early fungicidal activity(EFA) and clinical outcomes, and the comparative bioavailability of the MR formulation versus immediate release (IR) 5FC formulation in patients with HIV-associated CM in Tanzania. The consortium brings together renowned institutions and scientists fromSouth and Eastern Africa and Europe. In parallel with activities to develop new field adapted educational tools, focused work will be carried out to facilitate scale-up of implementation of WHO treatment guidelines in selected, trail-blazer countries in Sub-Saharan Africa with the greatest disease burden. Workshops with local MOHs will present the latest evidence and WHO policy on the management of CM. A demand forecasting tool will be implemented in collaboration of WHO, MOH representatives from LMICs with highest disease burden. This work is to complement the work by the cryptoMAG group on supply of essential medicines in collaboration with global funders, who are currently working on increased access to amphotericin B, fluconazole and standard formulations of 5FC in LMICs. This programme creates opportunities for collaboration and development of translation capacity through the implementation of Phase I and Phase II clinical trials, and further strengthen existing know-how inpharmacokinetic studies in the African setting.