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Sponsored by: |
National Institute of Allergy and Infectious Diseases (NIAID) |
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Information provided by: | National Institute of Allergy and Infectious Diseases (NIAID) |
ClinicalTrials.gov Identifier: | NCT00145249 |
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.
Condition | Intervention | Phase |
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Cryptococcal Meningitis |
Drug: Amphotericin B Drug: Fluconazole |
Phase II |
Study Type: | Interventional |
Study Design: | Treatment, Randomized, Open Label, Dose Comparison, Parallel Assignment, Safety/Efficacy Study |
Official Title: | A Phase II Randomized Trial of Amphotericin B Alone or Combined With Fluconazole in the Treatment of AIDS-Associated Cryptococcal Meningitis |
Enrollment: | 146 |
Study Start Date: | May 2005 |
Study Completion Date: | April 2008 |
Primary Completion Date: | April 2008 (Final data collection date for primary outcome measure) |
Arms | Assigned Interventions |
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Group 1: Active Comparator
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 amphoteicin B dose is continued beyond 14 days, fluconazole initiation will be delayed.
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Drug: Amphotericin B
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.
Drug: Fluconazole
Fluconazole 400 or 800 mg daily. Among subjects whose baseine weight is less than 40 kg, randomized fluconazole doses will be 200 mg/kg daily or 400 mg/kg daily.
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Group 2: Experimental
Amphotericin B 0.7mg/kg and the randomized dose of fluconazole at 400 mg/day for the first 14 days, then the randomized dose of fluconazole at 400mg/day respectively for an additional 8 weeks.
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Drug: Amphotericin B
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.
Drug: Fluconazole
Fluconazole 400 or 800 mg daily. Among subjects whose baseine weight is less than 40 kg, randomized fluconazole doses will be 200 mg/kg daily or 400 mg/kg daily.
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Group 3: Experimental
Amphotericin B 0.7mg/kg and the randomized dose of fluconazole at 800 mg/day for the first 14 days, then the randomized dose of fluconazole at 800mg/day respectively for an additional 8 weeks.
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Drug: Amphotericin B
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.
Drug: Fluconazole
Fluconazole 400 or 800 mg daily. Among subjects whose baseine weight is less than 40 kg, randomized fluconazole doses will be 200 mg/kg daily or 400 mg/kg daily.
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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 0.7mg/kg (IV) for 14 days followed by 8 weeks (56 days) of fluconazole at 400mg/day orally. The 2 investigational arms will include daily amphotericin B 0.7mg/kg (IV) and the randomized dose of fluconazole 400mg/day or 800 mg/day for the first 14 day, then the randomized dose of fluconazole at 400mg/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 definetly, 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.
Ages Eligible for Study: | 13 Years and older |
Genders Eligible for Study: | Both |
Accepts Healthy Volunteers: | No |
Inclusion Criteria:
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
Exclusion Criteria:
United States, Alabama | |
University of Alabama at Birmingham | |
Birmingham, Alabama, United States, 35233 | |
United States, California | |
UCLA Center For Vaccine Research | |
Torrance, California, United States, 90509 | |
University of Southern California | |
Los Angeles, California, United States, 90033 | |
United States, Colorado | |
University of Colorado | |
Denver, Colorado, United States, 80291-0238 | |
United States, Florida | |
University of Florida | |
Gainesville, Florida, United States, 32610 | |
University of Miami | |
Miami, Florida, United States, 33136-1096 | |
United States, Louisiana | |
Tulane University | |
New Orleans, Louisiana, United States, 70112 | |
United States, Michigan | |
Harper University Hospital | |
Detroit, Michigan, United States, 48201 | |
United States, Texas | |
VA Medical Center | |
Houston, Texas, United States, 77030 | |
The University of Texas Health Science Center at Houston | |
Houston, Texas, United States, 77030 | |
Thailand | |
Chiang Mai University | |
Chiang Mai, Thailand, 50200 | |
Ramathibodi Hospital, Mahidol University | |
Bangkok, Thailand, 10400 | |
Bamrasnaradura Institution | |
Nonthaburi, Thailand, 11000 | |
Khon Kaen University | |
Khon Kaen, Thailand, 40002 | |
Siriraj Hospital, Mahidol University | |
Bangkoknoi, Thailand, 10700 |
Responsible Party: | HHS/NIAID/DMID ( Robert Johnson ) |
Study ID Numbers: | 03-154, BAMSG 3-01 |
Study First Received: | September 2, 2005 |
Last Updated: | January 15, 2009 |
ClinicalTrials.gov Identifier: | NCT00145249 |
Health Authority: | Thailand: Ethical Committee; United States: Food and Drug Administration; United States: Federal Government; United States: Institutional Review Board |
Bacterial infections, HIV infection, cryptococcal meningitis |
Fluconazole Bacterial Infections Abelcet Amphotericin B Meningitis, Fungal Clotrimazole Miconazole Acquired Immunodeficiency Syndrome Tioconazole |
Central Nervous System Diseases Liposomal amphotericin B Meningitis Mycoses Central Nervous System Infections HIV Infections Meningitis, Cryptococcal Cryptococcosis |
Anti-Bacterial Agents Anti-Infective Agents Antiparasitic Agents Antiprotozoal Agents Antifungal Agents Therapeutic Uses |
Nervous System Diseases Antibiotics, Antifungal Amebicides Central Nervous System Fungal Infections Pharmacologic Actions |