Study Objectives
Primary Objective:
- To determine whether short-course high-dose L-AmB is as effective as 7-day amphotericin B deoxycholate-based treatment courses (current standard of care) in averting all-cause mortality in HIV-associated CM patients in a phase-III clinical endpoint trial.
Secondary Objectives:
- To determine the EFA in both treatment arms.
- To examine the proportions of patients in each arm with clinical and laboratory-defined grade III/IV adverse events; median % change from baseline in laboratory defined parameters, by treatment arm.
- To determine PK parameters and PK/PD associations of single high dose L-AmB.
- To determine health service costs by treatment arm.
- To determine all-cause mortality within the first 2 and 4 weeks.
- To determine whether short-course high-dose L-AmB is superior to 7-day amphotericin B-based treatment courses (current standard of care) in averting all-cause mortality.
- To determine rates of cryptococcal relapse / IRIS within the first 10 weeks by treatment arm.
- To determine rates of disability at 10 weeks by treatment arm.
Study Design: An open label phase III randomised controlled non-inferiority trial to compare single dose L-AmB treatment to 7-day amphotericin B deoxycholate based treatment for HIV-associated cryptococcal meningitis.
Study Population and Size: The study population will be HIV-seropositive patients admitted with a first episode of cryptococcal meningitis, identified by India ink staining of CSF or CrAg in CSF, at the participating centres, who fulfil the inclusion/exclusion criteria.
The trial recruited adult patients with a first episode of HIV-associated cryptococcal meningitis and enrolled 844 individuals with the Botswana site contributing 85 study participants from Princess Marina. After late exclusions, there were 407 participants in each arm who were included in the main analysis. No participants were lost to follow up.
Study Duration: 4 years
Sponsor: London School of Hygiene and Tropical Medicine.
The trial found that a single, high-dose of liposomal amphotericin B was as good as (“non-inferior”) to the current WHO recommended standard of care for HIV associated cryptococcal meningitis and much easier to give, requiring just one intravenous infusion compared to 7 days with standard therapy. The liposomal amphotericin B regimen was also associated with significantly fewer drug related effects such as anaemia, electrolyte abnormalities and intravenous line site infections. The two arms were well matched at baseline and represented the general population of patients presenting with cryptococcal meningitis. 60% were male, the median age was 37 years, and the majority had previously been prescribed antiretroviral therapy. The proportions of participants with confusion or reduced consciousness were similar as was the quantity of Cryptococcus around the brain.
There were 407 participants in each arm. At 10 weeks the mortality was 24.8% (101/407) in the AmBisome arm and 28.7% (117/407) in the control arm. The difference in the AmBisome arm compared to the control arm was -3.9% and it can be concluded that the AmBisome treatment was “non-inferior” to the control treatment. At the 10-week time point, when adjustments were made for differences between the two groups, it was found the AmBisome treatment may even be statistically superior to the control treatment. The rate of clearance of Cryptococcus from the cerebrospinal fluid of both arms was similar.
Drug related toxicity was more common in the control arm. Anaemia occurred in 13% of AmBisome participants compared to 41% in the control arm. The average drop in haemoglobin over the first week was 0.3g/dL in the AmBisome arm and 1.9g/dL in the control arm and as a result more participants in the control arm needed blood transfusions. There was also a difference in the impact on kidney function with an average increase in creatinine over the first week of 20.2% in the Ambisome arm and 49.7% in the control arm. Electrolyte abnormalities and infections around intravenous lines were also more common in the control arm.
