Treatment With Tamoxifen in Cryptococcal Meningitis

Study Overview
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Brief Summary
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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
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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.

Official Title
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A Randomized Trial of Tamoxifen Combined With Amphotericin B and Fluconazole for Cryptococcal Meningitis

Conditions
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Meningitis Streptococcal, Hiv, Meningitis, Meningoencephalitis

Intervention / Treatment
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* Drug: Tamoxifen
* Drug: Amphotericin B
* Drug: Fluconazole


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Tamoxifen augmented antifungal therapy<br>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) | Drug: Tamoxifen<br>* 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.<br>* Other names: Nolvadex - D;Drug: Amphotericin B<br>* Patients will receive amphotericin 1mg/kg/day i.v. once daily orally for the first 2 weeks.<br>* Other names: Amphotret;Drug: Fluconazole<br>* 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.<br>* Other names: Zolmed 200;|
| Active Comparator: Standard antifungal therapy<br>Amphotericin B 1mg/kg/day combined with fluconazole 800mg/day for the first 2 weeks followed by fluconazole 800mg/day for 8 weeks. | Drug: Amphotericin B<br>* Patients will receive amphotericin 1mg/kg/day i.v. once daily orally for the first 2 weeks.<br>* Other names: Amphotret;Drug: Fluconazole<br>* 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.<br>* Other names: Zolmed 200;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Early Fungicidal Activity (EFA), i.e. the rate of clearance of yeast from cerebrospinal fluid | In the trial, lumbar punctures are scheduled on days 1, 3, 7, 14, and additionally as clinically indicated. Whenever a lumbar puncture is performed, the study team will determine the amount of viable yeast in CSF through culture. Based on the patients' longitudinal quantitative yeast count measurements, EFA will be determined as previously described e.g. see N Engl J Med 2016; 374:542-54 | over the first 2 weeks following randomisation | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Survival until 10 weeks after randomization | International treatment guidelines recommend 10 weeks of high dose antifungal therapy for cryptococcal meningitis - an initial phase of amphotericin based induction therapy for 2 weeks followed by 8 weeks of moderate to high dose fluconazole. The rate of survival until this 10 week period of therapy is completed is a frequent endpoint in trials of treatment for cryptococcal meningitis. | 10 weeks after randomisation | 
| Disability at 10 weeks | Disability is an expected consequence of cryptococcal meningitis, including blindness, deafness and other focal neurological deficits. Neurological disability will be assessed using the modified Rankin score and the Two Simple Questions, and the results of each test combined and classified as good, intermediate, severe disability, or death, as we have previously published. | at 10 weeks | 
| Adverse events | The proportion of patients with any grade 3 or 4 adverse event, serious adverse event, or unexpected serious adverse event will be compared between treatment groups. | During hospital stay, an average of 10 weeks | 
| Rate of IRIS until 10 weeks (in HIV infected patients only) | The investigators will model the rate of IRIS over time with a cause-specific hazards model taking into account the competing risk of prior death. | until 10 weeks | 
| Rate of Cryptococcal meningitis relapse | A pragmatic definition of relapse will be used. This is defined as either intensification of antifungal therapy above that according to the study antifungal schedule, or readmission for treatment of cryptococcal disease. | until 10 weeks | 
| QT prolongation | Prolongation of the QT interval is a potential side-effect of both Tamoxifen and fluconazole, although it is not clear that either drug increases the risk of Torsade de Pointes, a potentially life-threatening arrhythmia. The QT interval will be estimated manually from 3 chest and 3 limb leads from a high resolution (50mm/sec) 12-lead ECG. The median value will be determined and used to calculate the corrected QT interval (QTc) using using Framingham's formula | During hospital stay, an average of 10 weeks | 
| Visual deficit at 10 weeks | Visual deficit occurs in 5-40% of patients with cryptococcal meningitis depending upon underlying immune status. The pathogenesis is unclear. The study team will compare the incidence of blindness and other visual deficit between treatment groups. Visual deficit will be assessed using a simple 6 point scale. | at 10 weeks | 
| Time to new neurological event or death until 10 weeks | A neurological event is defined as a fall in Glasgow coma score by ≥2 points for ≥2 days from the highest previously recorded Glasgow coma score (including baseline) or the occurrence of any of the following adverse events: cerebellar symptoms, coma, hemiplegia, paraplegia, seizures, cerebral herniation, new onset blindness or deafness, or cranial nerve palsy. | until 10 weeks | 
| Longitudinal measurements of intracranial pressure during the first 2 weeks | Intracranial pressure (ICP) will be measured at study entry, day 3, 7, and 14, and at other times as clinically indicated. The decline in raised intracranial pressure over the first 2 weeks will be modelled and compared between treatment arms. | during the first 2 weeks | 
| CD4 count at 10 weeks | CD4 count measurement is indicated in HIV infected patients, and CD4 lymphopenia has been described in HIV uninfected patients with cryptococcal meningitis. Moreover, Tamoxifen may reduce CD4 cell apoptosis which may be beneficial. | at 10 weeks | 
| Blood and CSF concentrations of amphotericin, Tamoxifen and fluconazole | All patients will undergo pharmacokinetic sampling to enable the description of the concentrations of Tamoxifen and fluconazole in plasma and CSF, and of amphotericin in blood, and relate these to the rate of clearance of yeast from CSF. | During hospital stay, an average of 10 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Tamoxifen, Cryptococcal meningitis, Cryptococcus neoformans, Human immunodeficiency virus