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Treatment With Tamoxifen in Cryptococcal Meningitis

Primary Purpose

Meningitis Streptococcal, Hiv, Meningitis

Status
Completed
Phase
Phase 2
Locations
Vietnam
Study Type
Interventional
Intervention
Tamoxifen
Amphotericin B
Fluconazole
Sponsored by
Oxford University Clinical Research Unit, Vietnam
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Meningitis Streptococcal focused on measuring Tamoxifen, Cryptococcal meningitis, Cryptococcus neoformans, Human immunodeficiency virus

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • Cho Ray Hospital
  • Hospital for Tropical Diseases
  • Oxford University Clinical Research Unit

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Active Comparator

Arm Label

Tamoxifen augmented antifungal therapy

Standard antifungal therapy

Arm Description

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)

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

Outcomes

Primary Outcome Measures

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

Secondary Outcome Measures

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.
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.
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.
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.
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.
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
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.
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.
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.
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.
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.

Full Information

First Posted
March 29, 2017
Last Updated
November 28, 2019
Sponsor
Oxford University Clinical Research Unit, Vietnam
Collaborators
Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam, Cho Ray Hospital, University of Liverpool, University of Rochester, Liverpool School of Tropical Medicine
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1. Study Identification

Unique Protocol Identification Number
NCT03112031
Brief Title
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

2. Study Status

Record Verification Date
November 2019
Overall Recruitment Status
Completed
Study Start Date
October 10, 2017 (Actual)
Primary Completion Date
July 17, 2018 (Actual)
Study Completion Date
July 17, 2018 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Oxford University Clinical Research Unit, Vietnam
Collaborators
Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam, Cho Ray Hospital, University of Liverpool, University of Rochester, Liverpool School of Tropical Medicine

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Meningitis Streptococcal, Hiv, Meningitis, Meningoencephalitis
Keywords
Tamoxifen, Cryptococcal meningitis, Cryptococcus neoformans, Human immunodeficiency virus

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
50 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Tamoxifen augmented antifungal therapy
Arm Type
Experimental
Arm Description
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)
Arm Title
Standard antifungal therapy
Arm Type
Active Comparator
Arm Description
Amphotericin B 1mg/kg/day combined with fluconazole 800mg/day for the first 2 weeks followed by fluconazole 800mg/day for 8 weeks.
Intervention Type
Drug
Intervention Name(s)
Tamoxifen
Other Intervention Name(s)
Nolvadex - D
Intervention Description
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.
Intervention Type
Drug
Intervention Name(s)
Amphotericin B
Other Intervention Name(s)
Amphotret
Intervention Description
Patients will receive amphotericin 1mg/kg/day i.v. once daily orally for the first 2 weeks.
Intervention Type
Drug
Intervention Name(s)
Fluconazole
Other Intervention Name(s)
Zolmed 200
Intervention Description
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.
Primary Outcome Measure Information:
Title
Early Fungicidal Activity (EFA), i.e. the rate of clearance of yeast from cerebrospinal fluid
Description
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
Time Frame
over the first 2 weeks following randomisation
Secondary Outcome Measure Information:
Title
Survival until 10 weeks after randomization
Description
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.
Time Frame
10 weeks after randomisation
Title
Disability at 10 weeks
Description
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.
Time Frame
at 10 weeks
Title
Adverse events
Description
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.
Time Frame
During hospital stay, an average of 10 weeks
Title
Rate of IRIS until 10 weeks (in HIV infected patients only)
Description
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.
Time Frame
until 10 weeks
Title
Rate of Cryptococcal meningitis relapse
Description
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.
Time Frame
until 10 weeks
Title
QT prolongation
Description
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
Time Frame
During hospital stay, an average of 10 weeks
Title
Visual deficit at 10 weeks
Description
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.
Time Frame
at 10 weeks
Title
Time to new neurological event or death until 10 weeks
Description
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.
Time Frame
until 10 weeks
Title
Longitudinal measurements of intracranial pressure during the first 2 weeks
Description
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.
Time Frame
during the first 2 weeks
Title
CD4 count at 10 weeks
Description
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.
Time Frame
at 10 weeks
Title
Blood and CSF concentrations of amphotericin, Tamoxifen and fluconazole
Description
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.
Time Frame
During hospital stay, an average of 10 weeks

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Jeremy Day, MD
Organizational Affiliation
Oxford University Clinical Research Unit
Official's Role
Principal Investigator
Facility Information:
Facility Name
Cho Ray Hospital
City
Ho Chi Minh City
Country
Vietnam
Facility Name
Hospital for Tropical Diseases
City
Ho Chi Minh City
Country
Vietnam
Facility Name
Oxford University Clinical Research Unit
City
Ho Chi Minh City
Country
Vietnam

12. IPD Sharing Statement

Plan to Share IPD
Undecided
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Treatment With Tamoxifen in Cryptococcal Meningitis

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