Clinical trial NCT03112031: Treatment With Tamoxifen in Cryptococcal Meningitis
Official title: A Randomized Trial of Tamoxifen Combined With Amphotericin B and Fluconazole for Cryptococcal Meningitis
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Meningitis Streptococcal
Hiv
Meningitis
Meningoencephalitis
Keywords: Tamoxifen
Cryptococcal meningitis
Cryptococcus neoformans
Human immunodeficiency virus
Lead sponsor: Oxford University Clinical Research Unit, Vietnam
Sponsor class: OTHER
Collaborators: name: Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam
name: Cho Ray Hospital
name: University of Liverpool
name: University of Rochester
name: Liverpool School of Tropical Medicine
First posted: 2017-04-13
Enrollment: 50
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.

Detailed description: 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.

Eligibility 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

Primary outcomes:
measure: Early Fungicidal Activity (EFA), i.e. the rate of clearance of yeast from cerebrospinal fluid
timeFrame: over the first 2 weeks following randomisation
Secondary outcomes:
measure: Survival until 10 weeks after randomization
timeFrame: 10 weeks after randomisation
measure: Disability at 10 weeks
timeFrame: at 10 weeks
measure: Adverse events
timeFrame: During hospital stay, an average of 10 weeks
measure: Rate of IRIS until 10 weeks (in HIV infected patients only)
timeFrame: until 10 weeks
measure: Rate of Cryptococcal meningitis relapse
timeFrame: until 10 weeks
measure: QT prolongation
timeFrame: During hospital stay, an average of 10 weeks
measure: Visual deficit at 10 weeks
timeFrame: at 10 weeks
measure: Time to new neurological event or death until 10 weeks
timeFrame: until 10 weeks
measure: Longitudinal measurements of intracranial pressure during the first 2 weeks
timeFrame: during the first 2 weeks
measure: CD4 count at 10 weeks
timeFrame: at 10 weeks
measure: Blood and CSF concentrations of amphotericin, Tamoxifen and fluconazole
timeFrame: During hospital stay, an average of 10 weeks
Other outcomes:
Locations:
city: Ho Chi Minh City
country: Vietnam
facility: Cho Ray Hospital
city: Ho Chi Minh City
country: Vietnam
facility: Hospital for Tropical Diseases
city: Ho Chi Minh City
country: Vietnam
facility: Oxford University Clinical Research Unit
Study officials:
affiliation: Oxford University Clinical Research Unit
name: Jeremy Day, MD
role: PRINCIPAL_INVESTIGATOR
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