An Open Label Randomized Controlled Phase IIb Trial to Determine the Safety of Oral Fluconazole in Combination With Flucytosine as Compared to Fluconazole Alone
An Open Label Randomized Controlled Phase IIb Trial to Determine the Safety of Oral Fluconazole in Combination With Flucytosine as Compared to Fluconazole Alone
The purpose of this study is to determine if treatment with two medicines in combination (fluconazole and flucytosine) is safe as compared with one medicine alone (fluconazole) for the treatment of an early infection with a fungus called cryptococcus.
Currently there is wide variation in practice and little evidence to guide the treatment of early cryptococcal infection in HIV-infected individuals with advanced immunosuppression. However, epidemiologic studies suggest that this may be a promising novel approach to decrease the mortality due to cryptococcal meningitis (CM), the second leading cause of death among HIV-infected individuals in many resource-limited settings. Screening asymptomatic HIV-infected individuals with advanced immunosuppression for serum cryptococcal antigen (CrAg) clearly identifies a population at high risk of CM and death and is a feasible screening method for resource-limited settings. However, screening with serum CrAg alone without additional diagnostic studies identifies a heterogeneous clinical population with early cryptococcal infection, many of whom already have sub-clinical meningeal infection or fungemia. The mainstay of anti-cryptococcal therapy in resource-limited settings is oral fluconazole though preliminary evidence suggests this is not an effective treatment. Thus, there is a critical need for potent therapies that (1) can be safely administered in resource-limited settings and (2) are effective in a heterogeneous population of HIV-infected individuals with advanced immunosuppression and early cryptococcal infection who are initiating anti-retroviral therapy (ART).
This single center, open-label, randomized Phase IIb study is being conducted to assess the safety and estimate the efficacy of oral fluconazole in combination with flucytosine for the treatment of early cryptococcal infection. The study will be based at two sites supported by Family AIDS Care and Education Services (FACES) in Western Kenya. A consecutive sample of 100 HIV-infected adults with CD4 cell count ≤100 cells/µl and serum CrAg titer ≥1:2 who have no signs or symptoms of severe, systemic cryptococcal infection will be enrolled. At enrollment, specimens from participants will be cultured for evidence of Cryptococcus neoformans. Individuals who meet inclusion and exclusion criteria and consent to participate in the study will be randomized to combination therapy with oral fluconazole (1200mg/day) plus flucytosine (100mg/kg/day) or fluconazole alone for the fourteen days of therapy. Subsequently both groups will receive anti-retroviral therapy as well as fluconazole 800mg/day for 8 weeks followed by 200mg/day. The primary safety endpoint will be the incidence of treatment-related adverse events and serious adverse events. The primary efficacy endpoint will be survival at 12 weeks.
In addition, we will offer additional diagnostic testing and aim for 50% participation, approximately 25 individuals from each arm. We will perform a battery of diagnostic tests including chest radiography, fungal cultures in blood, sputum, urine, stool and cerebrospinal fluid (CSF), cryptococcal antigen testing in the CSF, and gram stain, Ziehls-Nielsen stain and India Ink staining of CSF sediment. Anti-fungal susceptibility testing via broth microdilution and polymerase chain reaction serotyping and mating type analysis will be performed on clinical isolates.
Inclusion Criteria:
Exclusion Criteria: