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

NCT00145249 | Completed Phase 2 Results

• 2 other identifiers: 03-154BAMSG 3-01
• Study Type: interventional
• Target: 143
• Locations: 2 countries
• Sites: 15

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.

Conditions

Cryptococcal Meningitis

Keywords

Bacterial infections, HIV infection, cryptococcal meningitis

Outcome Measures

Primary Outcomes (2)

• 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.

  Day 100

• 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.

  Day 100

Secondary Outcomes (10)

• Number of Deaths

  14, 42, and 70 days

• Number of Subjects With Cerebrospinal Fluid (CSF) Culture Conversion at Multiple Time Points

  Baseline, 14, 42, and 70 days

• Number of Subjects Meeting the Key Efficacy Endpoint of Treatment Success

  14, 42, and 70 days

• Number of Subjects Reporting Immune Reconstitution Inflammatory Syndrome (IRIS)

  14, 42, and 70 days

• Mean Days of Hospitalization

  7, 14, 42, and 70 days

Study Arms (3)

Standard Therapy

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 Amphotericin B dose is continued beyond 14 days, fluconazole initiation will be delayed.

Drug: Amphotericin B; Drug: Fluconazole

Fluconazole Low Dose

EXPERIMENTAL

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.

Drug: Amphotericin B; Drug: Fluconazole

Fluconazole High Dose

EXPERIMENTAL

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.

Drug: Amphotericin B; Drug: Fluconazole

Interventions

Amphotericin B DRUG

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.

Fluconazole High Dose; Fluconazole Low Dose; Standard Therapy

Fluconazole DRUG

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.

Fluconazole High Dose; Fluconazole Low Dose; Standard Therapy

Eligibility Criteria

• Age: 13 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.
• 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.
• 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.

You may not qualify if:

• 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.)

Sponsors & Collaborators

• National Institute of Allergy and Infectious Diseases (NIAID): lead

Study Sites (15)

University of Alabama at Birmingham

Birmingham, Alabama, 35255, United States

Location

University of Southern California

Los Angeles, California, 90033, United States

Location

Harbor-UCLA Medical Center

Los Angeles, California, 90502, United States

Location

University of Colorado

Denver, Colorado, 80291-0238, United States

Location

University of Florida

Gainesville, Florida, 32610, United States

Location

University of Miami

Miami, Florida, 33136-1096, United States

Location

Tulane University Health Sciences Center

New Orleans, Louisiana, 70112, United States

Location

Harper University Hospital

Detroit, Michigan, 48201, United States

Location

Texas Medical Center - Michael E. DeBakey Veterans Affairs

Houston, Texas, 77030, United States

Location

The University of Texas Health Science Center at Houston

Houston, Texas, 77030, United States

Location

Ramathibodi Hospital, Mahidol University

Bangkok, 10400, Thailand

Location

Mahidol University - Siriraj Hospital - Medicine

Bangkok, 10700, Thailand

Location

Chiang Mai University

Chiang Mai, 50200, Thailand

Location

Khon Kaen University

Khon Kaen, 40002, Thailand

Location

Bamrasnaradura Institution

Nonthaburi, 11000, Thailand

Location

Related Publications (2)

• 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.

  PMID: 19441980 RESULT

• 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.

  PMID: 19897055 RESULT

MeSH Terms

Conditions

Meningitis, Cryptococcal; Bacterial Infections; HIV Infections

Interventions

Amphotericin B; Fluconazole

Condition Hierarchy (Ancestors)

Meningitis, Fungal; Central Nervous System Fungal Infections; Mycoses; Bacterial Infections and Mycoses; Infections; Cryptococcosis; Central Nervous System Infections; Central Nervous System Diseases; Nervous System Diseases; Meningitis; Neuroinflammatory Diseases; Blood-Borne Infections; Communicable Diseases; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; RNA Virus Infections; Virus Diseases; Genital Diseases; Urogenital Diseases; Immunologic Deficiency Syndromes; Immune System Diseases

Intervention Hierarchy (Ancestors)

Macrolides; Polyketides; Lactones; Organic Chemicals; Triazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds

Results Point of Contact

• Title: Peter G. Pappas, MD
• Organization: University of Alabama at Birmingham

pappas@uab.edu

205-934-9951

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: LTE60
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 2, 2005
• First Posted: September 5, 2005
• Study Start: May 1, 2005
• Primary Completion: April 1, 2008
• Study Completion: April 1, 2008
• Last Updated: May 16, 2012
• Results First Posted: June 23, 2010

Record last verified: 2009-10

Locations

TH (5); US (10)