Official Title: “A Phase II Randomized Trial of Amphotericin B Alone or Combined With Fluconazole in the Treatment of AIDS-Associated Cryptococcal Meningitis”

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.

Study Type: Interventional

Study Design: Treatment, Randomized, Open Label, Dose Comparison, Parallel Assignment, Safety/Efficacy Study

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.

Intervention(s) in this Clinical Trial

• 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.

Arms, Groups and Cohorts in this Clinical Trial

• Active Comparator: 1
  • 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.
• Experimental: 2
  • 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.
• Experimental: 3
  • 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.

Primary Measures

• Safety-incidence of grade 3-5 AEs that are definitely, probably, related to study drug.
  • Time Frame: Day 100
    Safety Issue?: Yes
• Safety-number of dose-limiting toxicities attributed to treatment regimens
  • Time Frame: Day 100
    Safety Issue?: Yes
• secondary analysis will include grade 3-5 adverse experiences that are definitely, probably or possibly related to study drugs.
  • Time Frame: Day 100
    Safety Issue?: Yes
• the number of dose-limiting toxicities attributed to the treatment regimens.
  • Time Frame: Day 100
    Safety Issue?: Yes

Secondary Measures

• Incidence of immune reconsitution inflammatory syndrome (IRIS)
  • Time Frame: 14, 42, and 70 days
    Safety Issue?: No
• Length of hospitalization
  • Time Frame: 14, 42, and 70 days
    Safety Issue?: No
• All-cause mortality
  • Time Frame: 14, 42, and 70 days
    Safety Issue?: No
• CSF culture conversion
  • Time Frame: 14, 42, and 70 days
    Safety Issue?: No
• CSF culture conversion at multiple time points
  • Time Frame: 14, 42, and 70 days
    Safety Issue?: No
• Treatment success will be a composite of the 3 mycologic and clinical measures: CSF culture conversion; neurologically stable or improved; and alive.
  • Time Frame: Day 100
    Safety Issue?: No

Inclusion Criteria:

• First episode of cryptococcal meningitis as evidenced by a positive 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 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 carnii 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 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 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% per year] when used consistently and correctly.) Emergency contraceptive treatment and coitus interruptus are not considered effective forms of contraception.
• Breastfeeding.
• A concurrent 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 barbituates.
• 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.

Gender Eligibility for this Clinical Trial: Both

Minimum Age for this Clinical Trial: 13 Years

Maximum Age for this Clinical Trial: N/A

Are Healthy Volunteers Accepted for this Clinical Trial?: No

Lead Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)

Information obtained from ClinicalTrials.gov on September 05, 2008

Link to the current ClinicalTrials.gov record. http://clinicaltrials.gov/show/NCT00145249

Study ID Number: 03-154

ClinicalTrials.gov Identifier: NCT00145249

Health Authority: United States: Federal Government