Treatment With Tamoxifen in Cryptococcal Meningitis

November 28, 2019 updated by: Oxford University Clinical Research Unit, Vietnam

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

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.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

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.

Study Type

Interventional

Enrollment (Actual)

50

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Vietnam
      • Ho Chi Minh City, Vietnam
        • Hospital for Tropical Diseases
      • Ho Chi Minh City, Vietnam
        • Oxford University Clinical Research Unit
      • Ho Chi Minh City, Vietnam
        • Cho Ray Hospital

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (ADULT, OLDER_ADULT)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: TREATMENT
  • Allocation: RANDOMIZED
  • Interventional Model: PARALLEL
  • Masking: NONE

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
EXPERIMENTAL: Tamoxifen augmented antifungal therapy
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
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
ACTIVE_COMPARATOR: 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: 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

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Early Fungicidal Activity (EFA), i.e. the rate of clearance of yeast from cerebrospinal fluid
Time Frame: over the first 2 weeks following randomisation
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
Time Frame: 10 weeks after randomisation
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
Time Frame: 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
Time Frame: During hospital stay, an average of 10 weeks
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)
Time Frame: until 10 weeks
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
Time Frame: until 10 weeks
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
Time Frame: During hospital stay, an average of 10 weeks
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
Time Frame: 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
Time Frame: 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
Time Frame: 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
Time Frame: 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
Time Frame: During hospital stay, an average of 10 weeks
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

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Oxford University Clinical Research Unit, Vietnam

Collaborators

University of Rochester
University of Liverpool
Liverpool School of Tropical Medicine
Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam
Cho Ray Hospital

Investigators

  • Principal Investigator: Jeremy Day, MD, Oxford University Clinical Research Unit

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (ACTUAL)

October 10, 2017

Primary Completion (ACTUAL)

July 17, 2018

Study Completion (ACTUAL)

July 17, 2018

Study Registration Dates

First Submitted

March 29, 2017

First Submitted That Met QC Criteria

April 7, 2017

First Posted (ACTUAL)

April 13, 2017

Study Record Updates

Last Update Posted (ACTUAL)

December 2, 2019

Last Update Submitted That Met QC Criteria

November 28, 2019

Last Verified

November 1, 2019

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 28CN

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

UNDECIDED

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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