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Amphotericin Alone or in Combination With Fluconazole for AIDS-Associated Meningitis

Primary Purpose

Cryptococcal Meningitis

Status
Completed
Phase
Phase 2
Locations
International
Study Type
Interventional
Intervention
Amphotericin B
Fluconazole
Sponsored by
National Institute of Allergy and Infectious Diseases (NIAID)
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Cryptococcal Meningitis focused on measuring Bacterial infections, HIV infection, cryptococcal meningitis

Eligibility Criteria

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

Inclusion Criteria: First episode of cryptococcal meningitis as evidenced by a positive cerebrospinal fluid (CSF) stain or cryptococcal antigen, CSF culture pending Documentation of proven diagnosis of HIV-1 infection by acceptable labs at any time in the past: this testing includes Enzyme-linked immunosorbent assay (ELISA) or approved rapid testing method with confirmation by Western blot, a second positive ELISA, a positive HIV antigen, or HIV RNA detection. OR -Presumptive diagnosis of HIV-1 by approved rapid testing method at screening. This testing must be confirmed by a second ELISA (or Western blot), a positive HIV antigen, or HIV RNA detection within 10 days of study entry. OR Presumptive HIV+. If serologic testing is not available, a history of an AIDS-defining illness (Category C, CDC, 1993) or any of the following conditions: extrapulmonary Pneumocystis carinii disease; multi-dermatomal herpes zoster (>10 lesions in a non-contiguous site); American trypanosomiasis (Chagas disease) of the CNS; Penicillium marneffei disease; visceral leishmaniasis; non-Hodgkin's lymphoma of any cell-type; Hodgkin's lymphoma; bartonellosis; microsporidiosis (>1 month's duration); nocardiosis; invasive aspergillosis; or Rhodococcus equi disease. Confirmation of HIV infection by lab testing, i.e., ELISA or approved rapid testing method with confirmation by Western blot, a second positive ELISA, a positive HIV antigen, or HIV RNA detection must be performed within 10 days of study entry. Subjects who are 13 years of age or greater. Baseline electrocardiogram (ECG) with QTc interval less than or equal to 500 milliseconds as determined by use of Fredericia's Correction formula. Ability of subject or legally authorized representative to give informed consent. For subjects who are unable to provide informed consent, sites will follow their own individual Institutional Review Board (IRB) policy regarding the informed consent process. Exclusion Criteria: Pregnancy. Urine or serum testing must be performed at study entry or within the 7 days prior to study entry. Women of childbearing potential unwilling to use a medically approved and highly effective form of birth control while on study drug and for 2 weeks after last dose. Acceptable forms of birth control include an intrauterine device (IUD), oral contraceptives, condoms, abstinence, injectable contraceptive, or any other highly effective means of birth control. (A highly effective method of birth control is defined as those which result in a low failure rate [i.e. less than 1 percent per year] when used consistently and correctly.) Emergency contraceptive treatment and coitus interruptus are not considered effective forms of contraception. Breastfeeding. A concurrent central nervous system (CNS) process that in the opinion of the investigator would interfere with assessment of response, such as lymphoma, toxoplasmosis, or tuberculosis. Other conditions that in the opinion of the investigator would jeopardize the safety of a subject participating in the study or would render the subject unable to comply with the study plan, such as homelessness or IV drug use. Estimated creatinine clearance of less than 50 mL/min. NOTE: Testing must be performed at study entry or within the 7 days prior to study entry. Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) greater than 5x the upper limit of normal or bilirubin greater than 2.5 x the upper limit of normal. Results from tests performed within the 7 days prior to study entry may be used. Known intolerance of or allergy to fluconazole or amphotericin B. Subjects unlikely to survive for 2 weeks. Coma. More than 3 days of any systemic antifungal therapy for this fungal infection, or the need for concurrent systemic antifungal therapy, including flucytosine or interferon-g. Subjects taking fluconazole at less than or equal to 200 mg/day for prophylaxis are not excluded. Inability to take oral medications. Subjects who have received the following drugs within 7 days of study enrollment: rifampin, rifamycin, rifabutin, phenytoin, carbamazepine, cyclosporin A, tacrolimus, sirolimus, or long-acting barbiturates. Subjects who are receiving nevirapine at baseline. Strong clinical suspicion of untreated active tuberculosis. (Patients on anti-TB therapy not including rifampin or rifamycin may be eligible.) Previous participation in this study or ongoing participation in another trial with an investigational drug. Prior case of cryptococcosis with diagnosed central nervous system involvement.

Sites / Locations

  • University of Alabama at Birmingham
  • University of Southern California
  • Harbor-UCLA Medical Center
  • University of Colorado
  • University of Florida
  • University of Miami
  • Tulane University Health Sciences Center
  • Harper University Hospital
  • Texas Medical Center - Michael E. DeBakey Veterans Affairs
  • The University of Texas Health Science Center at Houston
  • Ramathibodi Hospital, Mahidol University
  • Mahidol University - Siriraj Hospital - Medicine
  • Chiang Mai University
  • Khon Kaen University
  • Bamrasnaradura Institution

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Active Comparator

Experimental

Experimental

Arm Label

Standard Therapy

Fluconazole Low Dose

Fluconazole High Dose

Arm Description

Amphotericin B 0.7 mg/kg for 14 day followed by fluconazole 400 mg daily for 8 weeks. For subjects in the standard therapy arm whose Amphotericin B dose is continued beyond 14 days, fluconazole initiation will be delayed.

Amphotericin B 0.7 mg/kg and the randomized dose of fluconazole at 400 mg/day for the first 14 days, then the randomized dose of fluconazole at 400 mg/day respectively for an additional 8 weeks.

Amphotericin B 0.7 mg/kg and the randomized dose of fluconazole at 800 mg/day for the first 14 days, then the randomized dose of fluconazole at 800 mg/day respectively for an additional 8 weeks.

Outcomes

Primary Outcome Measures

Number of Grade 3-5 Adverse Experiences That Are Definitely or Probably Related to Study Drug
Events are reported by MedDRA Preferred Term. Grade 3 - Severe. Incapacitating; inability to perform usual activities and daily tasks; significantly affects clinical status; requires therapeutic intervention. Grade 4 - Life-threatening. AE is life-threatening. Grade 5 - Death. AE causes death.
Number of Dose-limiting Toxicities Attributed to Treatment Regimens
Events are reported by MedDRA Preferred Term. Dose limiting toxicities include events that resulted in study drug being adjusted, interrupted, or discontinued.

Secondary Outcome Measures

Number of Deaths
Number of deaths occurring on study. Day = Day relative to the first dose of study drug.
Number of Subjects With Cerebrospinal Fluid (CSF) Culture Conversion at Multiple Time Points
Number of subjects that have a negative fungal culture at Baseline, Day 14, Day 42, and Day 70.
Number of Subjects Meeting the Key Efficacy Endpoint of Treatment Success
Treatment success is defined as a composite of the 3 mycologic and clinical measures: CSF culture conversion; neurologically stable or improved; and alive
Number of Subjects Reporting Immune Reconstitution Inflammatory Syndrome (IRIS)
Number of subjects reporting immune reconstitution inflammatory syndrome (IRIS) following treatment. Day = Day relative to first dose of study drug
Mean Days of Hospitalization
Mean days of hospitalization. Includes days subject was hospitalized prior to study enrollment for current hospital stay.
Number of Cryptococcal Isolates With Antifungal Susceptibility
Isolates were collected at days 14 and 70 for assessment of antifungal susceptibility.
Mean Change in Neurological Exam Score From Baseline - Day 14
Neurological assessment by Mini-mental Status Exam (MMSE). This is collected as a continuous variable with values from 0-30; where lower scores indicate greater impairment.
Mean Change in Neurological Exam Score From Baseline - Day 42
Neurological assessment by Mini-mental Status Exam (MMSE). This is collected as a continuous variable with values from 0-30; where lower scores indicate greater impairment.
Mean Change in Neurological Exam Score From Baseline - Day 70
Neurological assessment by Mini-mental Status Exam (MMSE). This is collected as a continuous variable with values from 0-30; where lower scores indicate greater impairment.
Mean Change in Neurological Exam Score From Baseline - Day 168
Neurological assessment by Mini-mental Status Exam (MMSE). This is collected as a continuous variable with values from 0-30; where lower scores indicate greater impairment.

Full Information

First Posted
September 2, 2005
Last Updated
May 10, 2012
Sponsor
National Institute of Allergy and Infectious Diseases (NIAID)
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1. Study Identification

Unique Protocol Identification Number
NCT00145249
Brief Title
Amphotericin Alone or in Combination With Fluconazole for AIDS-Associated Meningitis
Official Title
A Phase II Randomized Trial of Amphotericin B Alone or Combined With Fluconazole in the Treatment of AIDS-Associated Cryptococcal Meningitis
Study Type
Interventional

2. Study Status

Record Verification Date
October 2009
Overall Recruitment Status
Completed
Study Start Date
May 2005 (undefined)
Primary Completion Date
April 2008 (Actual)
Study Completion Date
April 2008 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
National Institute of Allergy and Infectious Diseases (NIAID)

4. Oversight

5. Study Description

Brief Summary
This study will examine the effectiveness and safety of a combination treatment for cryptococcal meningitis, a fungal infection common in persons with acquired immune deficiency syndrome (AIDS) in the developing world. The standard initial treatment includes two medications: amphotericin B for 2 weeks followed by 8 weeks of fluconazole. This study will look at whether study participants recover more quickly and have fewer side effects if they are given both drugs at the same time for 2 weeks followed by 8 weeks of fluconazole as compared to the standard treatment. Participants will be followed for approximately 6 months from the time they are enrolled into the study.
Detailed Description
This study is designed to address the need for more effective antifungal therapy for cryptococcal meningitis. This is a prospective, randomized, open-label, multicenter phase II clinical trial of combination therapy for the treatment of acute cryptococcal meningitis in HIV-positive subjects. The primary study objectives will be to assess the safety and tolerability of the study drug regimens; and to determine whether the safety and efficacy of combination therapy supports development of a phase III trial of combination therapy, and if so, to select the most appropriate dose of fluconazole plus amphotericin B based on safety and efficacy to be evaluated in a subsequent phase III trial. Secondary study objectives include: comparing the efficacy of the study drug treatments at 2, 6, and 10 weeks (Days 14, 42, and 70); comparing the findings on detailed neurological examination between study arms at baseline and 2, 6, 10, and 24 weeks (6 months); assessing the proportion of subjects in each study arm that are alive at 6 months after initiation of study therapy; describing the effects of baseline clinical, neurological, and mycological characteristics on mycological failure at 2 and 10 weeks; measuring time to cerebrospinal fluid (CSF) culture negatively for each study arm; assessing the length of hospitalization in the treatment groups as a surrogate of cost efficacy; assessing the incidence of immune reconstitution inflammatory syndrome among all subjects receiving highly active antiretroviral therapy (HAART); and examining antifungal susceptibility of all cryptococcal isolates. Study participants will include 150 subjects ages 13 and older. Subjects will be randomly assigned to 1 of 3 treatment arms including 1 standard therapy and 2 investigational arms. The standard treatment arm will include amphotericin B 0.7 mg/kg (IV) for 14 days followed by 8 weeks (56 days) of fluconazole at 400 mg/day orally. The 2 investigational arms will include daily amphotericin B 0.7 mg/kg (IV) and the randomized dose of fluconazole 400 mg/day or 800 mg/day for the first 14 day, then the randomized dose of fluconazole at 400 mg/day or 800 mg/day respectively for an additional 8 weeks (56 days). At the completion of study therapy, all subjects will receive chronic suppressive therapy with oral fluconazole at a dose of at least 200 mg/day. The safety endpoints are considered to be the primary endpoints for this study. The safety assessment for each treatment arm will end at study day 100 for each subject. The key safety endpoint will be the incidence of adverse experiences of grade 3-5 (total and attributed to the treatment regimens). The primary safety endpoint will examine the incidence of grade 3-5 adverse experiences that are definitely or probably related to study drugs, while secondary analysis will include grade 3-5 adverse experiences that are, definitely probably or possibly related to study drugs. Another secondary safety endpoint will be the number of dose-limiting toxicities attributed to the treatment regimens. Key efficacy endpoint (treatment success) will be a composite of the following 3 mycologic and clinical measures after 14, 42, and 70 days of therapy: CSF culture conversion; neurologically stable or improved; and alive. Other secondary efficacy endpoints that will be evaluated descriptively are: CSF culture conversion at multiple time points; all-cause mortality; length of hospitalization; and incidence of immune reconstitution inflammatory syndrome.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Cryptococcal Meningitis
Keywords
Bacterial infections, HIV infection, cryptococcal meningitis

7. Study Design

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

8. Arms, Groups, and Interventions

Arm Title
Standard Therapy
Arm Type
Active Comparator
Arm Description
Amphotericin B 0.7 mg/kg for 14 day followed by fluconazole 400 mg daily for 8 weeks. For subjects in the standard therapy arm whose Amphotericin B dose is continued beyond 14 days, fluconazole initiation will be delayed.
Arm Title
Fluconazole Low Dose
Arm Type
Experimental
Arm Description
Amphotericin B 0.7 mg/kg and the randomized dose of fluconazole at 400 mg/day for the first 14 days, then the randomized dose of fluconazole at 400 mg/day respectively for an additional 8 weeks.
Arm Title
Fluconazole High Dose
Arm Type
Experimental
Arm Description
Amphotericin B 0.7 mg/kg and the randomized dose of fluconazole at 800 mg/day for the first 14 days, then the randomized dose of fluconazole at 800 mg/day respectively for an additional 8 weeks.
Intervention Type
Drug
Intervention Name(s)
Amphotericin B
Intervention Description
Amphotericin B 0.7 mg/kg IV for the first 14 days of treatment. This period may be extended up to an additional 7 days.
Intervention Type
Drug
Intervention Name(s)
Fluconazole
Intervention Description
Fluconazole 400 or 800 mg daily. Among subjects whose baseline weight is less than 40 kg, randomized fluconazole doses will be 200 mg/kg daily or 400 mg/kg daily.
Primary Outcome Measure Information:
Title
Number of Grade 3-5 Adverse Experiences That Are Definitely or Probably Related to Study Drug
Description
Events are reported by MedDRA Preferred Term. Grade 3 - Severe. Incapacitating; inability to perform usual activities and daily tasks; significantly affects clinical status; requires therapeutic intervention. Grade 4 - Life-threatening. AE is life-threatening. Grade 5 - Death. AE causes death.
Time Frame
Day 100
Title
Number of Dose-limiting Toxicities Attributed to Treatment Regimens
Description
Events are reported by MedDRA Preferred Term. Dose limiting toxicities include events that resulted in study drug being adjusted, interrupted, or discontinued.
Time Frame
Day 100
Secondary Outcome Measure Information:
Title
Number of Deaths
Description
Number of deaths occurring on study. Day = Day relative to the first dose of study drug.
Time Frame
14, 42, and 70 days
Title
Number of Subjects With Cerebrospinal Fluid (CSF) Culture Conversion at Multiple Time Points
Description
Number of subjects that have a negative fungal culture at Baseline, Day 14, Day 42, and Day 70.
Time Frame
Baseline, 14, 42, and 70 days
Title
Number of Subjects Meeting the Key Efficacy Endpoint of Treatment Success
Description
Treatment success is defined as a composite of the 3 mycologic and clinical measures: CSF culture conversion; neurologically stable or improved; and alive
Time Frame
14, 42, and 70 days
Title
Number of Subjects Reporting Immune Reconstitution Inflammatory Syndrome (IRIS)
Description
Number of subjects reporting immune reconstitution inflammatory syndrome (IRIS) following treatment. Day = Day relative to first dose of study drug
Time Frame
14, 42, and 70 days
Title
Mean Days of Hospitalization
Description
Mean days of hospitalization. Includes days subject was hospitalized prior to study enrollment for current hospital stay.
Time Frame
7, 14, 42, and 70 days
Title
Number of Cryptococcal Isolates With Antifungal Susceptibility
Description
Isolates were collected at days 14 and 70 for assessment of antifungal susceptibility.
Time Frame
Days 14 and 70
Title
Mean Change in Neurological Exam Score From Baseline - Day 14
Description
Neurological assessment by Mini-mental Status Exam (MMSE). This is collected as a continuous variable with values from 0-30; where lower scores indicate greater impairment.
Time Frame
Baseline and Day 14
Title
Mean Change in Neurological Exam Score From Baseline - Day 42
Description
Neurological assessment by Mini-mental Status Exam (MMSE). This is collected as a continuous variable with values from 0-30; where lower scores indicate greater impairment.
Time Frame
Baseline and Day 42
Title
Mean Change in Neurological Exam Score From Baseline - Day 70
Description
Neurological assessment by Mini-mental Status Exam (MMSE). This is collected as a continuous variable with values from 0-30; where lower scores indicate greater impairment.
Time Frame
Baseline and Day 70
Title
Mean Change in Neurological Exam Score From Baseline - Day 168
Description
Neurological assessment by Mini-mental Status Exam (MMSE). This is collected as a continuous variable with values from 0-30; where lower scores indicate greater impairment.
Time Frame
Baseline and Day 168

10. Eligibility

Sex
All
Minimum Age & Unit of Time
13 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: First episode of cryptococcal meningitis as evidenced by a positive cerebrospinal fluid (CSF) stain or cryptococcal antigen, CSF culture pending Documentation of proven diagnosis of HIV-1 infection by acceptable labs at any time in the past: this testing includes Enzyme-linked immunosorbent assay (ELISA) or approved rapid testing method with confirmation by Western blot, a second positive ELISA, a positive HIV antigen, or HIV RNA detection. OR -Presumptive diagnosis of HIV-1 by approved rapid testing method at screening. This testing must be confirmed by a second ELISA (or Western blot), a positive HIV antigen, or HIV RNA detection within 10 days of study entry. OR Presumptive HIV+. If serologic testing is not available, a history of an AIDS-defining illness (Category C, CDC, 1993) or any of the following conditions: extrapulmonary Pneumocystis carinii disease; multi-dermatomal herpes zoster (>10 lesions in a non-contiguous site); American trypanosomiasis (Chagas disease) of the CNS; Penicillium marneffei disease; visceral leishmaniasis; non-Hodgkin's lymphoma of any cell-type; Hodgkin's lymphoma; bartonellosis; microsporidiosis (>1 month's duration); nocardiosis; invasive aspergillosis; or Rhodococcus equi disease. Confirmation of HIV infection by lab testing, i.e., ELISA or approved rapid testing method with confirmation by Western blot, a second positive ELISA, a positive HIV antigen, or HIV RNA detection must be performed within 10 days of study entry. Subjects who are 13 years of age or greater. Baseline electrocardiogram (ECG) with QTc interval less than or equal to 500 milliseconds as determined by use of Fredericia's Correction formula. Ability of subject or legally authorized representative to give informed consent. For subjects who are unable to provide informed consent, sites will follow their own individual Institutional Review Board (IRB) policy regarding the informed consent process. Exclusion Criteria: Pregnancy. Urine or serum testing must be performed at study entry or within the 7 days prior to study entry. Women of childbearing potential unwilling to use a medically approved and highly effective form of birth control while on study drug and for 2 weeks after last dose. Acceptable forms of birth control include an intrauterine device (IUD), oral contraceptives, condoms, abstinence, injectable contraceptive, or any other highly effective means of birth control. (A highly effective method of birth control is defined as those which result in a low failure rate [i.e. less than 1 percent per year] when used consistently and correctly.) Emergency contraceptive treatment and coitus interruptus are not considered effective forms of contraception. Breastfeeding. A concurrent central nervous system (CNS) process that in the opinion of the investigator would interfere with assessment of response, such as lymphoma, toxoplasmosis, or tuberculosis. Other conditions that in the opinion of the investigator would jeopardize the safety of a subject participating in the study or would render the subject unable to comply with the study plan, such as homelessness or IV drug use. Estimated creatinine clearance of less than 50 mL/min. NOTE: Testing must be performed at study entry or within the 7 days prior to study entry. Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) greater than 5x the upper limit of normal or bilirubin greater than 2.5 x the upper limit of normal. Results from tests performed within the 7 days prior to study entry may be used. Known intolerance of or allergy to fluconazole or amphotericin B. Subjects unlikely to survive for 2 weeks. Coma. More than 3 days of any systemic antifungal therapy for this fungal infection, or the need for concurrent systemic antifungal therapy, including flucytosine or interferon-g. Subjects taking fluconazole at less than or equal to 200 mg/day for prophylaxis are not excluded. Inability to take oral medications. Subjects who have received the following drugs within 7 days of study enrollment: rifampin, rifamycin, rifabutin, phenytoin, carbamazepine, cyclosporin A, tacrolimus, sirolimus, or long-acting barbiturates. Subjects who are receiving nevirapine at baseline. Strong clinical suspicion of untreated active tuberculosis. (Patients on anti-TB therapy not including rifampin or rifamycin may be eligible.) Previous participation in this study or ongoing participation in another trial with an investigational drug. Prior case of cryptococcosis with diagnosed central nervous system involvement.
Facility Information:
Facility Name
University of Alabama at Birmingham
City
Birmingham
State/Province
Alabama
ZIP/Postal Code
35255
Country
United States
Facility Name
University of Southern California
City
Los Angeles
State/Province
California
ZIP/Postal Code
90033
Country
United States
Facility Name
Harbor-UCLA Medical Center
City
Los Angeles
State/Province
California
ZIP/Postal Code
90502
Country
United States
Facility Name
University of Colorado
City
Denver
State/Province
Colorado
ZIP/Postal Code
80291-0238
Country
United States
Facility Name
University of Florida
City
Gainesville
State/Province
Florida
ZIP/Postal Code
32610
Country
United States
Facility Name
University of Miami
City
Miami
State/Province
Florida
ZIP/Postal Code
33136-1096
Country
United States
Facility Name
Tulane University Health Sciences Center
City
New Orleans
State/Province
Louisiana
ZIP/Postal Code
70112
Country
United States
Facility Name
Harper University Hospital
City
Detroit
State/Province
Michigan
ZIP/Postal Code
48201
Country
United States
Facility Name
Texas Medical Center - Michael E. DeBakey Veterans Affairs
City
Houston
State/Province
Texas
ZIP/Postal Code
77030
Country
United States
Facility Name
The University of Texas Health Science Center at Houston
City
Houston
State/Province
Texas
ZIP/Postal Code
77030
Country
United States
Facility Name
Ramathibodi Hospital, Mahidol University
City
Bangkok
ZIP/Postal Code
10400
Country
Thailand
Facility Name
Mahidol University - Siriraj Hospital - Medicine
City
Bangkok
ZIP/Postal Code
10700
Country
Thailand
Facility Name
Chiang Mai University
City
Chiang Mai
ZIP/Postal Code
50200
Country
Thailand
Facility Name
Khon Kaen University
City
Khon Kaen
ZIP/Postal Code
40002
Country
Thailand
Facility Name
Bamrasnaradura Institution
City
Nonthaburi
ZIP/Postal Code
11000
Country
Thailand

12. IPD Sharing Statement

Citations:
PubMed Identifier
19441980
Citation
Pappas PG, Chetchotisakd P, Larsen RA, Manosuthi W, Morris MI, Anekthananon T, Sungkanuparph S, Supparatpinyo K, Nolen TL, Zimmer LO, Kendrick AS, Johnson P, Sobel JD, Filler SG. A phase II randomized trial of amphotericin B alone or combined with fluconazole in the treatment of HIV-associated cryptococcal meningitis. Clin Infect Dis. 2009 Jun 15;48(12):1775-83. doi: 10.1086/599112.
Results Reference
result
PubMed Identifier
19897055
Citation
Zimmer LO, Nolen TL, Pramanpol S, Wallace D, Walker ME, Pappas P, Chetchotisakd P. International collaboration between US and Thailand on a clinical trial of treatment for HIV-associated cryptococcal meningitis. Contemp Clin Trials. 2010 Jan;31(1):34-43. doi: 10.1016/j.cct.2009.11.002. Epub 2009 Nov 6.
Results Reference
result

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Amphotericin Alone or in Combination With Fluconazole for AIDS-Associated Meningitis

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