Trial | NCT03112031  Report issue

Title

Treatment With Tamoxifen in Cryptococcal Meningitis
A Randomized Trial of Tamoxifen Combined With Amphotericin B and Fluconazole for Cryptococcal Meningitis

  • Phase

    Phase 2

  • Study Type

    Interventional

  • Status

    Completed No Results Posted

  • Study Participants

    50
The purpose of this study is to develop initial efficacy, feasibility, and safety data regarding the use of Tamoxifen in combination with amphotericin B and fluconazole in the treatment of cryptococcal meningitis. The results of the study will inform the design and feasibility of a larger study powered to a survival endpoint. The study hypothesis is that adding tamoxifen to standard antifungal therapy increases the rate of clearance of yeast from cerebrospinal fluid. Increased rates of clearance of yeast from cerebrospinal fluid have previously been associated with improved clinical outcomes, including survival and disability.
A randomized, open-label trial with 2 parallel arms: standard antifungal therapy versus tamoxifen augmented antifungal therapy during the first 2 weeks (induction phase) of treatment. The study will recruit in two sites in Ho Chi Minh City: the Hospital for Tropical Diseases (HTD), and Cho Ray Hospital (CRH). 25 patients will be enrolled into the two study arms (intervention versus control). All anti-fungal administration will be directly observed by ward staff.

Intervention arm: Induction phase treatment (days 1-14): Tamoxifen will be given orally in a dose of 300mg/day for the first 14 days following randomization. It will be administered by nasogastric tube where patients are unconscious. In addition patients will receive amphotericin 1mg/kg once daily iv and fluconazole 800mg once daily orally. The tamoxifen will be administered in the morning combined with amphotericin and fluconazole dose.

Control arm: Induction phase treatment (days 1-14): Patients will receive amphotericin 1mg/kg/day combined with fluconazole 800mg once daily for the first 2 weeks. Amphotericin and fluconazole will be administered simultaneously.

The primary efficacy endpoint will be the rate of clearance of yeast cells from cerebrospinal fluid (CSF) over the first 2 weeks following randomisation. Patients will be followed for 10 weeks, which is conventional in clinical trials in cryptococcal meningitis. After the first 2 weeks of study treatment, all patients will receive fluconazole 800mg/day for 8 further weeks, until the study end. At this point, HIV infected patients will be switched to long term secondary prophylaxis with fluconazole 200mg/day as per standard practice. For HIV uninfected patients, the decision to continue antifungal treatment, and at which dose, will be made on a case by case basis by the attending physician in consultation with the patient.
Study Started
Oct 10
2017
Primary Completion
Jul 17
2018
Study Completion
Jul 17
2018
Last Update
Dec 02
2019

Drug Tamoxifen

Tamoxifen will be given orally in a dose of 300mg/day for the first 14 days following randomization. It will be administered by nasogastric tube where patients are unconscious. The Tamoxifen will be administered in the morning combined with amphotericin and fluconazole dose.

  • Other names: Nolvadex - D

Drug Amphotericin B

Patients will receive amphotericin 1mg/kg/day i.v. once daily orally for the first 2 weeks.

  • Other names: Amphotret

Drug Fluconazole

Patients will receive fluconazole 800mg once daily orally for the first 2 weeks. Amphotericin and fluconazole will be administered simultaneously. After the first 2 weeks of study treatment, all patients will receive fluconazole 800mg/day for 8 further weeks, until the study end.

  • Other names: Zolmed 200

Tamoxifen augmented antifungal therapy Experimental

Tamoxifen 300mg/day for 2 weeks, combined with standard antifungal therapy (amphotericin B 1mg/kg/day combined with fluconazole 800mg/day for the first 2 weeks followed by fluconazole 800mg/day for 8 weeks)

Standard antifungal therapy Active Comparator

Amphotericin B 1mg/kg/day combined with fluconazole 800mg/day for the first 2 weeks followed by fluconazole 800mg/day for 8 weeks.

Criteria 

Inclusion Criteria:

Age ≥ 18 years

Cryptococcal meningitis (CM) defined as a syndrome consistent with CM and one or more of:

positive CSF India ink (budding encapsulated yeasts),
C. neoformans cultured from CSF or blood,
positive cryptococcal antigen Lateral Flow Antigen Test (LFA) in CSF
Informed consent to participate given by patient or acceptable representative
Known HIV infection status, or patient agrees to HIV testing on this admission

Exclusion Criteria:

Pregnancy or breast-feeding
History of thromboembolic disease such as pulmonary embolism or deep venous thrombosis
On anti-coagulant medication
On medication known to prolong the QT interval other than fluconazole, such as fluoroquinolones or antidepressants.
Known cardiac conduction defect including long QT syndromes
QTc at baseline > 500ms
Currently receiving treatment for cryptococcal meningitis and having received > 4 days of anti-cryptococcal meningitis therapy
Known allergy to Tamoxifen
Currently or history of receiving treatment with Tamoxifen for breast cancer or other indication
Current or history of uterine cancer including endometrial cancer and uterine sarcoma
Renal failure (defined as creatinine >3*ULN (upper limit of normal), despite adequate hydration)
Failure to consent - the patient, or if they are incapacitated, their responsible relative, declines to enter the study
Allergy to amphotericin B or fluconazole
No Results Posted