Treatment With Tamoxifen in Cryptococcal Meningitis

NCT03112031 | Completed Phase 2 DMC

• 1 other identifier: 28CN
• Study Type: interventional
• Target: 50
• Locations: 1 country
• Sites: 3

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.

Conditions

Meningitis Streptococcal; Hiv; Meningitis; Meningoencephalitis

Keywords

Tamoxifen; Cryptococcal meningitis; Cryptococcus neoformans; Human immunodeficiency virus

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (11)

• Survival until 10 weeks after randomization

  10 weeks after randomisation

• Disability at 10 weeks

  at 10 weeks

• Adverse events

  During hospital stay, an average of 10 weeks

• Rate of IRIS until 10 weeks (in HIV infected patients only)

  until 10 weeks

• Rate of Cryptococcal meningitis relapse

  until 10 weeks

Study Arms (2)

Tamoxifen augmented antifungal therapy

EXPERIMENTAL

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; Drug: Amphotericin B; Drug: Fluconazole

Standard antifungal therapy

ACTIVE COMPARATOR

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; Drug: Fluconazole

Interventions

Tamoxifen DRUG

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.

Also known as: Nolvadex - D

Tamoxifen augmented antifungal therapy

Amphotericin B DRUG

Patients will receive amphotericin 1mg/kg/day i.v. once daily orally for the first 2 weeks.

Also known as: Amphotret

Standard antifungal therapy; Tamoxifen augmented antifungal therapy

Fluconazole DRUG

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.

Also known as: Zolmed 200

Standard antifungal therapy; Tamoxifen augmented antifungal therapy

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Oxford University Clinical Research Unit, Vietnam: lead
• Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam: collaborator
• Cho Ray Hospital: collaborator
• University of Liverpool: collaborator
• University of Rochester: collaborator
• Liverpool School of Tropical Medicine: collaborator

Study Sites (3)

Cho Ray Hospital

Ho Chi Minh City, Vietnam

Location

Hospital for Tropical Diseases

Ho Chi Minh City, Vietnam

Location

Oxford University Clinical Research Unit

Ho Chi Minh City, Vietnam

Location

Related Publications (57)

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MeSH Terms

Conditions

Acquired Immunodeficiency Syndrome; Meningitis; Meningoencephalitis; Meningitis, Cryptococcal; Cryptococcosis

Interventions

Tamoxifen; Amphotericin B; Fluconazole

Condition Hierarchy (Ancestors)

HIV Infections; Blood-Borne Infections; Communicable Diseases; Infections; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; RNA Virus Infections; Virus Diseases; Slow Virus Diseases; Genital Diseases; Urogenital Diseases; Immunologic Deficiency Syndromes; Immune System Diseases; Neuroinflammatory Diseases; Nervous System Diseases; Central Nervous System Viral Diseases; Central Nervous System Infections; Encephalitis; Brain Diseases; Central Nervous System Diseases; Meningitis, Fungal; Central Nervous System Fungal Infections; Mycoses; Bacterial Infections and Mycoses

Intervention Hierarchy (Ancestors)

Stilbenes; Benzylidene Compounds; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Macrolides; Polyketides; Lactones; Triazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds

Study Officials

• Jeremy Day, MD

  Oxford University Clinical Research Unit

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: March 29, 2017
• First Posted: April 13, 2017
• Study Start: October 10, 2017
• Primary Completion: July 17, 2018
• Study Completion: July 17, 2018
• Last Updated: December 2, 2019

Record last verified: 2019-11

Locations

VN (3)