An open label randomized controlled trial of tamoxifen combined with amphotericin B and fluconazole for cryptococcal meningitis
2021
Nguyen Thi Thuy Ngan | Nhat Thanh Hoang Le | Nguyen Ngo Vi Vi | Ninh Thi Thanh Van | Nguyen Thi Hoang Mai | Duong Van Anh | Phan Hai Trieu | Nguyen Phu Huong Lan | Nguyen Hoan Phu | Nguyen Van Vinh Chau | David G Lalloo | William Hope | Justin Beardsley | Nicholas J White | Ronald Geskus | Guy E Thwaites | Damian Krysan | Luong Thi Hue Tai | Evelyne Kestelyn | Tran Quang Binh | Le Quoc Hung | Nguyen Le Nhu Tung | Jeremy N Day
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.
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