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A Randomized Double Blind Protocol Comparing Amphotericin B With Flucytosine to Amphotericin B Alone Followed by a Comparison of Fluconazole and Itraconazole in the Treatment of Acute Cryptococcal Meningitis

Primary Purpose

Meningitis, Cryptococcal, HIV Infections

Status
Completed
Phase
Not Applicable
Locations
United States
Study Type
Interventional
Intervention
Itraconazole
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, Cryptococcosis, Drug Evaluation, Drug Therapy, Combination, Fluconazole, Flucytosine, Acquired Immunodeficiency Syndrome, Amphotericin B, Brain Diseases

Eligibility Criteria

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

Inclusion Criteria Concurrent Medication: Allowed: Interruption of myelosuppressive therapies and/or administration of erythropoietin, at discretion of investigator, to maintain hemoglobin = or > 7 g/dl. Adjunctive corticosteroids may be administered during the triazole phase for patients who develop Pneumocystis carinii pneumonia and meet the prescribed criteria. Hydrocortisone, not to exceed 50 mg/day, during the amphotericin phase. Aerosolized pentamidine or systemic chemoprophylaxis for Pneumocystis carinii pneumonia should be given to all patients with a CD4 count < 200 cells/mm3. Antiretroviral drugs (including zidovudine (AZT), didanosine (ddI), dideoxycytidine (ddC)) after patient has tolerated oral triazole for one week (after 3 weeks of study treatment). Maintenance treatment (except for rifamycins) for other opportunistic infections such as cytomegalovirus (CMV) retinitis, cerebral toxoplasmosis or mycobacterial infections, provided that their hematologic and hepatic values are stable and they meet the entry criteria. Concurrent Treatment: Allowed: - Transfusion, at discretion of investigator, to maintain hemoglobin = or > 7 g/dl. Patients must have: HIV infection. Primary episode of acute cryptococcal meningitis. Willing to participate in the study for a full 10 weeks and either be able to give informed consent or have a family member or guardian able to give informed consent. Prior Medication: Allowed: Fluconazole prophylaxis, not exceeding 200 mg/day. Risk Behavior: Allowed: - History of high-risk behavior for HIV infection (bisexual or homosexual men, intravenous drug abusers) and their sexual partners. Exclusion Criteria Co-existing Condition: Patients with the following conditions or symptoms are excluded: Inability to take oral medication (if necessary, flucytosine and flucytosine placebo may be administered via nasogastric tube during the amphotericin phase). History of hypersensitivity to imidazole or triazole compounds. Active hepatitis (viral, drug-induced, or other) defined by progressive worsening of hepatic enzymes to grade 3 or 4 toxicity on at least two occasions. Comatose. Concurrent CNS disease which, in the opinion of the investigator, would interfere with assessment of response. Concurrent Medication: Excluded: Continued treatment with H2 blockers (ranitidine (Zantac), cimetidine (Tagamet), omeprazole (Prilosec), nizatidine (Axid), famotidine (Pepcid)). Antacids and didanosine (ddI) within 2 hours of triazole administration. Rifampin, rifabutin (Ansamycin), and other rifamycin derivatives, phenytoin (Dilantin), phenobarbital, or carbamazepine (Tegretol). Other systemic antifungal agents. Prior Medication: Excluded: Amphotericin, > 1 mg/kg, or fluconazole or ketoconazole, > 1200 mg, as prior treatment for current primary episode of acute cryptococcal meningitis or treatment started for this episode more than 72 hours prior to enrollment into study. Phenytoin (Dilantin), carbamazepine (Tegretol), phenobarbital, rifabutin (Ansamycin), rifampin or other rifamycins within the last 15 days. Patients may not have: Inability to take oral medication (if necessary, flucytosine and flucytosine placebo may be administered via nasogastric tube during the amphotericin phase). History of hypersensitivity to imidazole or triazole compounds. Active hepatitis. Patients who are comatose. Concurrent CNS disease which, in the opinion of the investigator, would interfere with assessment of response.

Sites / Locations

  • USC CRS
  • Ucsf Aids Crs
  • Univ. of Miami AIDS CRS
  • Univ. of Hawaii at Manoa, Leahi Hosp.
  • Northwestern University CRS
  • Indiana Univ. School of Medicine, Infectious Disease Research Clinic
  • Methodist Hosp. of Indiana
  • Tulane Med. Ctr. - Charity Hosp. of New Orleans, ACTU
  • Massachusetts General Hospital ACTG CRS
  • Bmc Actg Crs
  • Beth Israel Deaconess Med. Ctr., ACTG CRS
  • St. Louis ConnectCare, Infectious Diseases Clinic
  • Washington U CRS
  • SUNY - Buffalo, Erie County Medical Ctr.
  • Beth Israel Med. Ctr. (Mt. Sinai)
  • Cornell University A2201
  • Univ. of Rochester ACTG CRS
  • Unc Aids Crs
  • Carolinas HealthCare System, Carolinas Med. Ctr.
  • Regional Center for Infectious Disease, Wendover Medical Center CRS
  • Univ. of Cincinnati CRS
  • The Ohio State Univ. AIDS CRS
  • Hosp. of the Univ. of Pennsylvania CRS
  • Pitt CRS

Outcomes

Primary Outcome Measures

Secondary Outcome Measures

Full Information

First Posted
November 2, 1999
Last Updated
October 26, 2021
Sponsor
National Institute of Allergy and Infectious Diseases (NIAID)
Collaborators
Washington University School of Medicine
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1. Study Identification

Unique Protocol Identification Number
NCT00000639
Brief Title
A Randomized Double Blind Protocol Comparing Amphotericin B With Flucytosine to Amphotericin B Alone Followed by a Comparison of Fluconazole and Itraconazole in the Treatment of Acute Cryptococcal Meningitis
Official Title
A Randomized Double Blind Protocol Comparing Amphotericin B With Flucytosine to Amphotericin B Alone Followed by a Comparison of Fluconazole and Itraconazole in the Treatment of Acute Cryptococcal Meningitis
Study Type
Interventional

2. Study Status

Record Verification Date
October 2021
Overall Recruitment Status
Completed
Study Start Date
undefined (undefined)
Primary Completion Date
undefined (undefined)
Study Completion Date
September 1997 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
National Institute of Allergy and Infectious Diseases (NIAID)
Collaborators
Washington University School of Medicine

4. Oversight

5. Study Description

Brief Summary
To evaluate the effectiveness and safety of amphotericin B plus flucytosine (5-fluorocytosine) compared to amphotericin B alone for a first episode of acute cryptococcal meningitis in AIDS patients, and to compare the effectiveness and safety of fluconazole versus itraconazole. At least 10 percent of patients with a low CD4 count and HIV infection will develop meningitis due to Cryptococcus neoformans. More effective treatments than the standard therapy need to be explored.
Detailed Description
At least 10 percent of patients with a low CD4 count and HIV infection will develop meningitis due to Cryptococcus neoformans. More effective treatments than the standard therapy need to be explored. Patients are selected by a randomization process to take amphotericin B intravenously (in the vein), for 14 days, and either placebo (ineffective substance) or flucytosine for 14 days. Then patients are again selected by a randomization process to take either (1) fluconazole for a total of 8 weeks plus itraconazole placebo; or (2) itraconazole for a total of 8 weeks plus fluconazole placebo.

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, Cryptococcosis, Drug Evaluation, Drug Therapy, Combination, Fluconazole, Flucytosine, Acquired Immunodeficiency Syndrome, Amphotericin B, Brain Diseases

7. Study Design

Primary Purpose
Treatment
Study Phase
Not Applicable
Masking
Double
Enrollment
400 (false)

8. Arms, Groups, and Interventions

Intervention Type
Drug
Intervention Name(s)
Itraconazole
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
13 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria Concurrent Medication: Allowed: Interruption of myelosuppressive therapies and/or administration of erythropoietin, at discretion of investigator, to maintain hemoglobin = or > 7 g/dl. Adjunctive corticosteroids may be administered during the triazole phase for patients who develop Pneumocystis carinii pneumonia and meet the prescribed criteria. Hydrocortisone, not to exceed 50 mg/day, during the amphotericin phase. Aerosolized pentamidine or systemic chemoprophylaxis for Pneumocystis carinii pneumonia should be given to all patients with a CD4 count < 200 cells/mm3. Antiretroviral drugs (including zidovudine (AZT), didanosine (ddI), dideoxycytidine (ddC)) after patient has tolerated oral triazole for one week (after 3 weeks of study treatment). Maintenance treatment (except for rifamycins) for other opportunistic infections such as cytomegalovirus (CMV) retinitis, cerebral toxoplasmosis or mycobacterial infections, provided that their hematologic and hepatic values are stable and they meet the entry criteria. Concurrent Treatment: Allowed: - Transfusion, at discretion of investigator, to maintain hemoglobin = or > 7 g/dl. Patients must have: HIV infection. Primary episode of acute cryptococcal meningitis. Willing to participate in the study for a full 10 weeks and either be able to give informed consent or have a family member or guardian able to give informed consent. Prior Medication: Allowed: Fluconazole prophylaxis, not exceeding 200 mg/day. Risk Behavior: Allowed: - History of high-risk behavior for HIV infection (bisexual or homosexual men, intravenous drug abusers) and their sexual partners. Exclusion Criteria Co-existing Condition: Patients with the following conditions or symptoms are excluded: Inability to take oral medication (if necessary, flucytosine and flucytosine placebo may be administered via nasogastric tube during the amphotericin phase). History of hypersensitivity to imidazole or triazole compounds. Active hepatitis (viral, drug-induced, or other) defined by progressive worsening of hepatic enzymes to grade 3 or 4 toxicity on at least two occasions. Comatose. Concurrent CNS disease which, in the opinion of the investigator, would interfere with assessment of response. Concurrent Medication: Excluded: Continued treatment with H2 blockers (ranitidine (Zantac), cimetidine (Tagamet), omeprazole (Prilosec), nizatidine (Axid), famotidine (Pepcid)). Antacids and didanosine (ddI) within 2 hours of triazole administration. Rifampin, rifabutin (Ansamycin), and other rifamycin derivatives, phenytoin (Dilantin), phenobarbital, or carbamazepine (Tegretol). Other systemic antifungal agents. Prior Medication: Excluded: Amphotericin, > 1 mg/kg, or fluconazole or ketoconazole, > 1200 mg, as prior treatment for current primary episode of acute cryptococcal meningitis or treatment started for this episode more than 72 hours prior to enrollment into study. Phenytoin (Dilantin), carbamazepine (Tegretol), phenobarbital, rifabutin (Ansamycin), rifampin or other rifamycins within the last 15 days. Patients may not have: Inability to take oral medication (if necessary, flucytosine and flucytosine placebo may be administered via nasogastric tube during the amphotericin phase). History of hypersensitivity to imidazole or triazole compounds. Active hepatitis. Patients who are comatose. Concurrent CNS disease which, in the opinion of the investigator, would interfere with assessment of response.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
van der Horst C
Official's Role
Study Chair
First Name & Middle Initial & Last Name & Degree
Saag M
Official's Role
Study Chair
Facility Information:
Facility Name
USC CRS
City
Los Angeles
State/Province
California
ZIP/Postal Code
90033
Country
United States
Facility Name
Ucsf Aids Crs
City
San Francisco
State/Province
California
ZIP/Postal Code
94110
Country
United States
Facility Name
Univ. of Miami AIDS CRS
City
Miami
State/Province
Florida
ZIP/Postal Code
33136
Country
United States
Facility Name
Univ. of Hawaii at Manoa, Leahi Hosp.
City
Honolulu
State/Province
Hawaii
Country
United States
Facility Name
Northwestern University CRS
City
Chicago
State/Province
Illinois
ZIP/Postal Code
60611
Country
United States
Facility Name
Indiana Univ. School of Medicine, Infectious Disease Research Clinic
City
Indianapolis
State/Province
Indiana
ZIP/Postal Code
46202
Country
United States
Facility Name
Methodist Hosp. of Indiana
City
Indianapolis
State/Province
Indiana
ZIP/Postal Code
46202
Country
United States
Facility Name
Tulane Med. Ctr. - Charity Hosp. of New Orleans, ACTU
City
New Orleans
State/Province
Louisiana
ZIP/Postal Code
70112
Country
United States
Facility Name
Massachusetts General Hospital ACTG CRS
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02114
Country
United States
Facility Name
Bmc Actg Crs
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02118
Country
United States
Facility Name
Beth Israel Deaconess Med. Ctr., ACTG CRS
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02215
Country
United States
Facility Name
St. Louis ConnectCare, Infectious Diseases Clinic
City
Saint Louis
State/Province
Missouri
Country
United States
Facility Name
Washington U CRS
City
Saint Louis
State/Province
Missouri
Country
United States
Facility Name
SUNY - Buffalo, Erie County Medical Ctr.
City
Buffalo
State/Province
New York
ZIP/Postal Code
14215
Country
United States
Facility Name
Beth Israel Med. Ctr. (Mt. Sinai)
City
New York
State/Province
New York
ZIP/Postal Code
10003
Country
United States
Facility Name
Cornell University A2201
City
New York
State/Province
New York
ZIP/Postal Code
10021
Country
United States
Facility Name
Univ. of Rochester ACTG CRS
City
Rochester
State/Province
New York
ZIP/Postal Code
14642
Country
United States
Facility Name
Unc Aids Crs
City
Chapel Hill
State/Province
North Carolina
ZIP/Postal Code
27599
Country
United States
Facility Name
Carolinas HealthCare System, Carolinas Med. Ctr.
City
Charlotte
State/Province
North Carolina
Country
United States
Facility Name
Regional Center for Infectious Disease, Wendover Medical Center CRS
City
Greensboro
State/Province
North Carolina
ZIP/Postal Code
27401
Country
United States
Facility Name
Univ. of Cincinnati CRS
City
Cincinnati
State/Province
Ohio
ZIP/Postal Code
45267
Country
United States
Facility Name
The Ohio State Univ. AIDS CRS
City
Columbus
State/Province
Ohio
ZIP/Postal Code
43210
Country
United States
Facility Name
Hosp. of the Univ. of Pennsylvania CRS
City
Philadelphia
State/Province
Pennsylvania
ZIP/Postal Code
19104
Country
United States
Facility Name
Pitt CRS
City
Pittsburgh
State/Province
Pennsylvania
ZIP/Postal Code
15213
Country
United States

12. IPD Sharing Statement

Citations:
PubMed Identifier
9203426
Citation
van der Horst CM, Saag MS, Cloud GA, Hamill RJ, Graybill JR, Sobel JD, Johnson PC, Tuazon CU, Kerkering T, Moskovitz BL, Powderly WG, Dismukes WE. Treatment of cryptococcal meningitis associated with the acquired immunodeficiency syndrome. National Institute of Allergy and Infectious Diseases Mycoses Study Group and AIDS Clinical Trials Group. N Engl J Med. 1997 Jul 3;337(1):15-21. doi: 10.1056/NEJM199707033370103.
Results Reference
background
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
Citation
Powderly WG, Tuazon C, Cloud GA, Saag MS, Van Der Horst C. Serum and CSF cryptococcal antigen in management of cryptococcal meningitis in AIDS. Conf Retroviruses Opportunistic Infect. 1997 Jan 22-26;4th:66 (abstract no 6)
Results Reference
background

Learn more about this trial

A Randomized Double Blind Protocol Comparing Amphotericin B With Flucytosine to Amphotericin B Alone Followed by a Comparison of Fluconazole and Itraconazole in the Treatment of Acute Cryptococcal Meningitis

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