An open label randomized controlled trial of tamoxifen combined with amphotericin B and fluconazole for cryptococcal meningitis
Nguyen Thi Thuy Ngan, Le Thanh Hoang Nhat, Nguyen Ngo Vi, Ninh Thi Thanh Van, Nguyen Thi Hoang, Duong Van Anh, Phan Trieu, Nguyen Phu Huong Lan, Nguyen Hoan Phu, Nguyễn Văn Vĩnh Châu, David G. Lalloo, William Hope, Justin Beardsley, Nicholas J. White, Ronald B. Geskus, Guy Thwaites, Damian J. Krysan, Luong Thi Hue Tai, Evelyne Kestelyn, Trần Quang Bình, Le Quoc Hung, Nguyen Le Nhu Tung, Jeremy Day
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: 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.