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Multi-center Comparison of Fluconazole (UK-49,858) and Amphotericin B as Treatment for Acute Cryptococcal Meningitis

Primary Purpose

Meningitis, Cryptococcal, HIV Infections

Status
Completed
Phase
Not Applicable
Locations
United States
Study Type
Interventional
Intervention
Flucytosine
Fluconazole
Amphotericin B
Sponsored by
National Institute of Allergy and Infectious Diseases (NIAID)
About
Eligibility
Locations
Outcomes
Full info

About this trial

This is an interventional treatment trial for Meningitis, Cryptococcal focused on measuring AIDS-Related Opportunistic Infections, Meningitis, Injections, Intravenous, Cryptococcus neoformans, Cryptococcosis, Drug Therapy, Combination, Fluconazole, Administration, Oral, Acquired Immunodeficiency Syndrome, Amphotericin B

Eligibility Criteria

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

Inclusion Criteria Concurrent Medication: Allowed: Immunosuppressant therapy. Cyclosporin plasma concentrations should be monitored and appropriate dosage adjustments made when used with amphotericin B or fluconazole. Antiviral therapy. Prophylaxis for Pneumocystis carinii pneumonia. Treatment of intercurrent opportunistic infection as long as no investigational agent, or approved agent for an investigational indication, is used. Antipyretics, hydrocortisone, or meperidine to prevent or ameliorate side effects associated with amphotericin B. Concurrent Treatment: Allowed: - Radiation therapy for mucocutaneous Kaposi's sarcoma. Patients must have: Written informed consent obtained from the patient or from the patient's legal guardian. One of the following: (1) Tentative identification of Cryptococcus neoformans in culture of lumbar cerebrospinal fluid (CSF). Results of baseline cultures need not be available when therapy is begun, but therapy is discontinued if the baseline CSF culture is later found to be negative for C. neoformans, or (2) Clinical and CSF findings (cell count, protein, glucose) compatible with cryptococcal meningitis plus one of the following: (a) Positive CSF India ink examination, (b) Culture or biopsy evidence of extraneural cryptococcal infection, (c) Positive serum of CSF cryptococcal antigen test, or increase in titer for previously treated patients with suspected relapse, or (d) Biopsy evidence of central nervous system cryptococcal infection. Treatment status of either no prior systemic antifungal therapy for cryptococcosis or relapse after prior therapy. The success of prior therapy must have been documented by negative CSF culture at the end of therapy. Prior Medication: Allowed within 4 weeks of study entry: - Successful prior therapy for cryptococcosis, but no more than 1 mg/kg/week amphotericin B. Allowed: Immunosuppressant therapy. Antiviral therapy. Prophylaxis for Pneumocystis carinii pneumonia. Exclusion Criteria Co-existing Condition: Excluded: Acute or chronic meningitis based on any etiology other than cryptococcosis. History of allergy to or intolerance of imidazoles, or amphotericin B. Moderate or severe liver disease defined as any one or more of the following: SGOT or SGPT > 5 x upper limit of normal, total bilirubin > 2.5 mg/dl, prothrombin time > 5 seconds over control, or alkaline phosphatase > 2 x upper limit of normal. Comatose patients. Concurrent Medication: Excluded: Drugs with low therapeutic ratios that undergo hepatic metabolism may not be used with fluconazole until possible drug interactions have been clarified. Coumarin-type anticoagulants. Oral hypoglycemics. Barbiturates. Immunostimulants. Investigational drugs or approved (licensed) drugs for investigational indications. Systemic antifungal agent other than the assigned study drug. Concurrent Treatment: Excluded: Lymphocyte replacement. Prior Medication: Excluded within 4 weeks of study entry: More than 1 mg/kg/week amphotericin B. Patients unlikely to survive more than 2 weeks.

Sites / Locations

  • Univ of Miami School of Medicine
  • Tulane Univ School of Medicine
  • Bronx Municipal Hosp Ctr/Jacobi Med Ctr
  • Mem Sloan - Kettering Cancer Ctr
  • Univ of North Carolina
  • Julio Arroyo

Outcomes

Primary Outcome Measures

Secondary Outcome Measures

Full Information

First Posted
November 2, 1999
Last Updated
March 11, 2011
Sponsor
National Institute of Allergy and Infectious Diseases (NIAID)
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1. Study Identification

Unique Protocol Identification Number
NCT00000708
Brief Title
Multi-center Comparison of Fluconazole (UK-49,858) and Amphotericin B as Treatment for Acute Cryptococcal Meningitis
Official Title
Multi-center Comparison of Fluconazole (UK-49,858) and Amphotericin B as Treatment for Acute Cryptococcal Meningitis
Study Type
Interventional

2. Study Status

Record Verification Date
July 1991
Overall Recruitment Status
Completed
Study Start Date
undefined (undefined)
Primary Completion Date
July 1991 (Actual)
Study Completion Date
undefined (undefined)

3. Sponsor/Collaborators

Name of the Sponsor
National Institute of Allergy and Infectious Diseases (NIAID)

4. Oversight

5. Study Description

Brief Summary
To compare the safety and effectiveness of fluconazole (FCZ) and amphotericin B (AMB), alone or in combination with flucytosine (FLC), as treatment for acute cryptococcal meningitis in patients who have not been treated previously or who have relapsed after a previous successful treatment. Cryptococcal meningitis is an important cause of disease and death among patients with AIDS. Usually AMB is given either alone or with FLC to patients with this infection, but these treatments are not always effective and both have toxic effects. Animal studies and preliminary studies in humans show that FCZ is active in cryptococcal meningitis and suggest that it may be less toxic than either AMB or FLC.
Detailed Description
Cryptococcal meningitis is an important cause of disease and death among patients with AIDS. Usually AMB is given either alone or with FLC to patients with this infection, but these treatments are not always effective and both have toxic effects. Animal studies and preliminary studies in humans show that FCZ is active in cryptococcal meningitis and suggest that it may be less toxic than either AMB or FLC. Patients accepted into the study are randomly assigned to FCZ or AMB. Patients assigned to FCZ take FCZ by mouth daily for 10 weeks. Patients assigned to AMB are given intravenous injections of AMB daily for 6-10 weeks. Non-AIDS patients assigned to AMB also take FLC by mouth daily. The use of FLC in patients with AIDS is decided on an individual basis. Patients with AIDS who respond satisfactorily to FCZ receive maintenance therapy to prevent relapse for an additional 12 months. Patients with AIDS who respond to AMB may qualify for another Pfizer Central Research protocol. Patients without AIDS who respond to therapy are observed for 6 months for relapse. During therapy, samples of blood and cerebrospinal fluid (by lumbar puncture) are taken periodically in order to evaluate the effectiveness of the drug treatments and to identify possible toxic effects.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Meningitis, Cryptococcal, HIV Infections
Keywords
AIDS-Related Opportunistic Infections, Meningitis, Injections, Intravenous, Cryptococcus neoformans, Cryptococcosis, Drug Therapy, Combination, Fluconazole, Administration, Oral, Acquired Immunodeficiency Syndrome, Amphotericin B

7. Study Design

Primary Purpose
Treatment
Study Phase
Not Applicable
Interventional Study Model
Parallel Assignment
Enrollment
120 (false)

8. Arms, Groups, and Interventions

Intervention Type
Drug
Intervention Name(s)
Flucytosine
Intervention Type
Drug
Intervention Name(s)
Fluconazole
Intervention Type
Drug
Intervention Name(s)
Amphotericin B

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria Concurrent Medication: Allowed: Immunosuppressant therapy. Cyclosporin plasma concentrations should be monitored and appropriate dosage adjustments made when used with amphotericin B or fluconazole. Antiviral therapy. Prophylaxis for Pneumocystis carinii pneumonia. Treatment of intercurrent opportunistic infection as long as no investigational agent, or approved agent for an investigational indication, is used. Antipyretics, hydrocortisone, or meperidine to prevent or ameliorate side effects associated with amphotericin B. Concurrent Treatment: Allowed: - Radiation therapy for mucocutaneous Kaposi's sarcoma. Patients must have: Written informed consent obtained from the patient or from the patient's legal guardian. One of the following: (1) Tentative identification of Cryptococcus neoformans in culture of lumbar cerebrospinal fluid (CSF). Results of baseline cultures need not be available when therapy is begun, but therapy is discontinued if the baseline CSF culture is later found to be negative for C. neoformans, or (2) Clinical and CSF findings (cell count, protein, glucose) compatible with cryptococcal meningitis plus one of the following: (a) Positive CSF India ink examination, (b) Culture or biopsy evidence of extraneural cryptococcal infection, (c) Positive serum of CSF cryptococcal antigen test, or increase in titer for previously treated patients with suspected relapse, or (d) Biopsy evidence of central nervous system cryptococcal infection. Treatment status of either no prior systemic antifungal therapy for cryptococcosis or relapse after prior therapy. The success of prior therapy must have been documented by negative CSF culture at the end of therapy. Prior Medication: Allowed within 4 weeks of study entry: - Successful prior therapy for cryptococcosis, but no more than 1 mg/kg/week amphotericin B. Allowed: Immunosuppressant therapy. Antiviral therapy. Prophylaxis for Pneumocystis carinii pneumonia. Exclusion Criteria Co-existing Condition: Excluded: Acute or chronic meningitis based on any etiology other than cryptococcosis. History of allergy to or intolerance of imidazoles, or amphotericin B. Moderate or severe liver disease defined as any one or more of the following: SGOT or SGPT > 5 x upper limit of normal, total bilirubin > 2.5 mg/dl, prothrombin time > 5 seconds over control, or alkaline phosphatase > 2 x upper limit of normal. Comatose patients. Concurrent Medication: Excluded: Drugs with low therapeutic ratios that undergo hepatic metabolism may not be used with fluconazole until possible drug interactions have been clarified. Coumarin-type anticoagulants. Oral hypoglycemics. Barbiturates. Immunostimulants. Investigational drugs or approved (licensed) drugs for investigational indications. Systemic antifungal agent other than the assigned study drug. Concurrent Treatment: Excluded: Lymphocyte replacement. Prior Medication: Excluded within 4 weeks of study entry: More than 1 mg/kg/week amphotericin B. Patients unlikely to survive more than 2 weeks.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Armstrong D
Official's Role
Study Chair
Facility Information:
Facility Name
Univ of Miami School of Medicine
City
Miami
State/Province
Florida
ZIP/Postal Code
331361013
Country
United States
Facility Name
Tulane Univ School of Medicine
City
New Orleans
State/Province
Louisiana
ZIP/Postal Code
70112
Country
United States
Facility Name
Bronx Municipal Hosp Ctr/Jacobi Med Ctr
City
Bronx
State/Province
New York
ZIP/Postal Code
10461
Country
United States
Facility Name
Mem Sloan - Kettering Cancer Ctr
City
New York
State/Province
New York
ZIP/Postal Code
10021
Country
United States
Facility Name
Univ of North Carolina
City
Chapel Hill
State/Province
North Carolina
ZIP/Postal Code
275997215
Country
United States
Facility Name
Julio Arroyo
City
West Columbia
State/Province
South Carolina
ZIP/Postal Code
29169
Country
United States

12. IPD Sharing Statement

Citations:
PubMed Identifier
8722838
Citation
Powderly WG. Recent advances in the management of cryptococcal meningitis in patients with AIDS. Clin Infect Dis. 1996 May;22 Suppl 2:S119-23. doi: 10.1093/clinids/22.supplement_2.s119.
Results Reference
background
PubMed Identifier
8075272
Citation
Powderly WG, Cloud GA, Dismukes WE, Saag MS. Measurement of cryptococcal antigen in serum and cerebrospinal fluid: value in the management of AIDS-associated cryptococcal meningitis. Clin Infect Dis. 1994 May;18(5):789-92. doi: 10.1093/clinids/18.5.789.
Results Reference
background
PubMed Identifier
1727236
Citation
Saag MS, Powderly WG, Cloud GA, Robinson P, Grieco MH, Sharkey PK, Thompson SE, Sugar AM, Tuazon CU, Fisher JF, et al. Comparison of amphotericin B with fluconazole in the treatment of acute AIDS-associated cryptococcal meningitis. The NIAID Mycoses Study Group and the AIDS Clinical Trials Group. N Engl J Med. 1992 Jan 9;326(2):83-9. doi: 10.1056/NEJM199201093260202.
Results Reference
background

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Multi-center Comparison of Fluconazole (UK-49,858) and Amphotericin B as Treatment for Acute Cryptococcal Meningitis

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