Background: The AMBITION-cm trial aimed to define a novel treatment approach for HIV associated cryptococcal meningitis. I aimed to explore inclusion and representation in trials for cryptococcal meningitis, and to critically interpret qualitative data around clinical trials for life-threatening illnesses. I then used ethnographic methods to explore the lived experience of those involved in the AMBITION-cm trial. Methods: I systematically searched research databases and performed a meta-analysis of clinical trials for cryptococcal meningitis, and a critical interpretive synthesis of qualitative data collected from participants in trials from life-threatening illnesses. I embedded an ethnographic study within AMBITION-cm in Botswana and Uganda, utilising in-depth interviews and direct observations and analysed data thematically. Results: In the meta-analysis, 39 papers were included. Trials had evolved with the epidemiology of cryptococcal meningitis, however severe and relapse cases were underrepresented, as were female researchers and researchers from LMICs in authorship. Twenty-two papers were included in the critical interpretive synthesis to produce a synthetic construct describing how the life-threatening illness overwhelmingly impacts decision making. Eighty-nine individuals were recruited into the ethnographic study. Pathways to care were extremely convoluted and I identified multiple recommendations for improvement. Participants had a complex decision-making process to navigate, and decisions were made based on a therapeutic expectation from the trial. The AMBITION-cm regimen was acceptable to patients and providers. Conclusions: Trials for cryptococcal meningitis are typically conducted in line with the epidemiology of the disease however some groups are under-represented. There are significant gaps in routine healthcare systems for people living with advanced HIV. Challenges in managing cryptococcal meningitis may be averted by the convenience and acceptability of the AMBITION-cm regimen. The life-threatening nature of an illness has a critical impact on the experience of enrolling into a trial and the decision to enrol in AMBITION-cm was based on a therapeutic expectation.