An open label randomized controlled trial of tamoxifen combined with amphotericin B and fluconazole for cryptococcal meningitis

Abstract

Background: Cryptococcal meningitis has high mortality. Flucytosine is a key treatment but is expensive and rarely available. The anticancer agent tamoxifen has synergistic anti-cryptococcal activity with amphotericin in vitro. It is off-patent, cheap, and widely available. We performed a trial to determine its therapeutic potential.

Methods: Open label randomized controlled trial. Participants received standard care - amphotericin combined with fluconazole for the first 2 weeks - or standard care plus tamoxifen 300 mg/day. The primary end point was Early Fungicidal Activity (EFA) - the rate of yeast clearance from cerebrospinal fluid (CSF). Trial registration https://clinicaltrials.gov/ct2/show/NCT03112031.

Results: Fifty patients were enrolled (median age 34 years, 35 male). Tamoxifen had no effect on EFA (-0.48log10 colony-forming units/mL/CSF control arm versus -0.49 tamoxifen arm, difference -0.005log10CFU/ml/day, 95% CI: -0.16, 0.15, p=0.95). Tamoxifen caused QTc prolongation.

Conclusions: High-dose tamoxifen does not increase the clearance rate of Cryptococcus from CSF. Novel, affordable therapies are needed.

Funding: The trial was funded through the Wellcome Trust Asia Programme Vietnam Core Grant 106680 and a Wellcome Trust Intermediate Fellowship to JND grant number WT097147MA.

Keywords: HIV; Viet Nam; cryptococcal meningitis; cryptococcus gattii; cryptococcus neoformans; infectious disease; medicine; microbiology; randomised controlled trial.

Figure 1.. Trial flow chart: enrollment, randomization, and follow-up.

Figure 2.. The impact of addition of tamoxifen to standard treatment on (A) the rate of sterilzation of cerebrospinal fluid, and (B) survival until 10 weeks after randomisation.

(A) Decline in fungal count in CSF as measured in colony-forming units (CFU) per milliliter over the first 2 weeks of treatment by treatment arm. Data from individual patients are shown in grey lines. Bold blue lines show estimated mean with 95% credible intervals (shaded band) of CSF fungal counts based on the joint model described in the statistical analysis. The rate of decline was −0.49 log10CFU/ml/day in patients receiving tamoxifen versus −0.48 log10CFU/ml/day in control patients. The horizontal dashed lines represent the value of detection limit (4.5 CFU/ml). The fitted line crosses the horizontal dashed lines of the detection limit value after day 8 because 25% and 75% of patients had fungal counts under the detection limit at days 8 and 15, respectively. (B) Kaplan-Meier survival cures for each study arm over the 10-week study period. Seven death events occurred in the control arm versus 8 in the tamoxifen intervention arm by 10 weeks (estimated risk 27% versus 34%, absolute risk difference = 6.5%) (95% Confidence Interval −19.2 to 32.1%, p = 0.62).

Figure 3.. Change in QTc interval over the first 2 weeks of treatment by study arm.

Faint lines display change in individual patient QTcs; bold lines display the estimated mean and shaded bands the 95% Confidence Intervals; blue = control arm, red = tamoxifen arm. The maximum median difference in the QTc intervals between study arms immediately prior to drug administration was 37.07 ms (95% CI: 21.09, 53.04) and occurred on day 9 of the study. The largest difference in median QTc 2 hr post-drug administration was 33.44 ms (95% CI: 18.67, 48.21) and occurred on day 8 of the study. Additional details regarding change in QTc are provided in the Supplementary Appendix.

Appendix 1—figure 1.. Graphical representation of differences in QTc between study arm of ther first 2 weeks of the trial.

The bold lines and the shaded bands represent the estimated mean difference with 95% Confidence Interval of QTc between two study arms. The output of the fitted linear mixed effect model computes the differences in QTc between study arms by study day, separately for pre-dose and 2 hours post-dose measurements.