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Treatment With Tamoxifen in Cryptococcal Meningitis

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ClinicalTrials.gov Identifier: NCT03112031
Recruitment Status : Completed
First Posted : April 13, 2017
Last Update Posted : December 2, 2019
Sponsor:
Collaborators:
Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam
Cho Ray Hospital
University of Liverpool
University of Rochester
Liverpool School of Tropical Medicine
Information provided by (Responsible Party):
Oxford University Clinical Research Unit, Vietnam

Tracking Information
First Submitted Date  ICMJE March 29, 2017
First Posted Date  ICMJE April 13, 2017
Last Update Posted Date December 2, 2019
Actual Study Start Date  ICMJE October 10, 2017
Actual Primary Completion Date July 17, 2018   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: April 7, 2017)
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
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: April 12, 2017)
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
Original Secondary Outcome Measures  ICMJE
 (submitted: April 7, 2017)
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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
  • 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.
  • 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.
  • 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 14 days will be modelled and compared between treatment arms.
  • 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.
  • 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.
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Treatment With Tamoxifen in Cryptococcal Meningitis
Official Title  ICMJE A Randomized Trial of Tamoxifen Combined With Amphotericin B and Fluconazole for Cryptococcal Meningitis
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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Meningitis Streptococcal
  • Hiv
  • Meningitis
  • Meningoencephalitis
Intervention  ICMJE
  • 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 Name: Nolvadex - D
  • Drug: Amphotericin B
    Patients will receive amphotericin 1mg/kg/day i.v. once daily orally for the first 2 weeks.
    Other Name: 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 Name: Zolmed 200
Study Arms  ICMJE
  • 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)
    Interventions:
    • Drug: Tamoxifen
    • Drug: Amphotericin B
    • Drug: Fluconazole
  • 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.
    Interventions:
    • Drug: Amphotericin B
    • Drug: Fluconazole
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: April 7, 2017)
50
Original Estimated Enrollment  ICMJE Same as current
Actual Study Completion Date  ICMJE July 17, 2018
Actual Primary Completion Date July 17, 2018   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Vietnam
Removed Location Countries United Kingdom,   United States
 
Administrative Information
NCT Number  ICMJE NCT03112031
Other Study ID Numbers  ICMJE 28CN
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: Undecided
Responsible Party Oxford University Clinical Research Unit, Vietnam
Study Sponsor  ICMJE Oxford University Clinical Research Unit, Vietnam
Collaborators  ICMJE
  • Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam
  • Cho Ray Hospital
  • University of Liverpool
  • University of Rochester
  • Liverpool School of Tropical Medicine
Investigators  ICMJE
Principal Investigator: Jeremy Day, MD Oxford University Clinical Research Unit
PRS Account Oxford University Clinical Research Unit, Vietnam
Verification Date November 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP