High-Dose Fluconazole for the Treatment of Cryptococcal Meningitis in HIV-Infected Individuals

NCT00885703 | Completed Phase 1 Results

• 6 other identifiers: A5225 (HiFLAC)10149ACTG A5225HiFLACA5225/HiFLACA5225
• Study Type: interventional
• Target: 168
• Locations: 8 countries
• Sites: 10

Brief Summary

Cryptococcal meningitis (CM) is an infection of the membranes covering the brain and spinal cord, caused by the fungus Cryptococcus neoformans. CM most often affects people with compromised immune systems, like those with advanced HIV infection. This study explored the safety, tolerability, and therapeutic effect of a new treatment regimen with high-dose fluconazole for management of CM in HIV-infected patients.

Conditions

Cryptococcal Meningitis; HIV Infections

Keywords

CM; HIV; Meningitis

Outcome Measures

Primary Outcomes (4)

• Number of Participants Who Discontinued Study-provided High Dose Fluconazole or Ampho B

  Discontinuation of study-provided high dose fluconazole at or by week 10 Discontinuation of study-provided ampho B at or by week 2 Discontinuation includes discontinuing for any reason, including progression of symptoms, death, etc.

  Measured from study entry through Week10

• Categorized Quantitative Culture Results

  Count of participants who were CM negative (had no cryptococcal growth), CM negative after switching treatment (switched from Fluconazole to Ampho B or vice versa and later became CM negative), CM positive, Died, Lost to follow-up. Note: CM positive means continued to have cryptococcal growth.

  At entry, Week 2, and Week 10

• Change in Log10 Quantitative CSF Culture Results

  Change in quantitative CSF (cerebrospinal fluid) cultures. Note: No further CSF specimens are drawn following a negative culture. Thus, only week 2 CSF cultures are considered in this analysis.

  Entry and Week 2

• Kaplan Meier (KM) Proportion of Participant Mortality

  Kaplan Meier Proportion of participants who died over study with 90% Confidence Intervals.

  Measured from study entry through Week 24

Secondary Outcomes (7)

• Results of the Neurological Examination

  Measured at study entry, Week 2, and Week 10

• Results of Functional Status Evaluation

  Measured 6 weeks before enrollment, at study entry, at Week 10, and at Week 24

• Length of Hospitalization

  Measured from study entry through Week 10

• Number of Hospital Admissions

  Measured from study entry through Week 24

• Number of Participants With Progression of Symptoms

  Measured from study entry through Week 24

Study Arms (7)

Stage 1, Fluconazole 1200mg

EXPERIMENTAL

Participants receive Fluconazole 1200mg induction dose in Stage 1

Drug: Fluconazole

Stage 1, Fluconazole 1600mg

EXPERIMENTAL

Participants receive Fluconazole 1600mg induction dose in Stage 1

Drug: Fluconazole

Stage 1, Fluconazole 2000mg

EXPERIMENTAL

Participants receive Fluconazole 2000mg induction dose in Stage 1

Drug: Fluconazole

Stage 1, Ampho B

ACTIVE COMPARATOR

Participants receive Amphotericin B followed by Fluconazole in Stage 1

Drug: Fluconazole; Drug: Amphotericin B

Stage 2, Fluconazole 1600mg

EXPERIMENTAL

Participants receive Fluconazole 1600mg induction dose in Stage 2

Drug: Fluconazole

Stage 2, Fluconazole 2000mg

EXPERIMENTAL

Participants receive Fluconazole 2000mg induction dose in Stage 2

Drug: Fluconazole

Stage 2, Ampho B

ACTIVE COMPARATOR

Participants receive Amphotericin B followed by Fluconazole in Stage 2

Drug: Fluconazole; Drug: Amphotericin B

Interventions

Fluconazole DRUG

Step 1: \[For participants randomized to Fluconazole\] Induction dose of daily treatment of fluconazole given orally (adjusted according to weight). Step 2: \[For participants randomized to Ampho B only\] If participant is intolerant to Ampho B, participant transitions to fluconazole dosage of 400-800mg daily given orally. Step 3: If participant has a negative culture before week 10, participant transitions to consolidation therapy at dosage of 400mg daily given orally. Step 4: At week 10, participant transitions to maintenance therapy at dosage of 200mg daily given orally.

Also known as: Diflucan

Stage 1, Ampho B; Stage 1, Fluconazole 1200mg; Stage 1, Fluconazole 1600mg; Stage 1, Fluconazole 2000mg; Stage 2, Ampho B; Stage 2, Fluconazole 1600mg; Stage 2, Fluconazole 2000mg

Amphotericin B DRUG

Step 1: \[For participants randomized to Ampho B\] Ampho B given intravenously for approximately 2 weeks at a dosage of 0.7 to 1.0 mg/kg, dependent on a participant's weight

Also known as: Amphotericin B deoxycholate, Ampho B, Amphocin, Fungizone, AmBisome, Abelecet, Amphotec

Stage 1, Ampho B; Stage 2, Ampho B

Eligibility Criteria

• Age: 16 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• CM documented either by a positive CSF cryptococcal culture, a positive CSF India ink preparation, or a positive CSF cryptococcal antigen latex agglutination test within 7 days prior to entry. More information on this criterion can be found in the protocol.
• CSF collection for quantitative cryptococcal culture within 72 hours prior to study entry or planned to be performed at study entry
• HIV-1 infection documented by any licensed rapid HIV test or HIV enzyme or chemiluminescence immunoassay (E/CIA) test kit at any time prior to study entry and confirmed by or within 10 days after study entry by a licensed Western blot or a second antibody test by a method other than the initial rapid HIV and/or E/CIA, by HIV-1 antigen, or by plasma HIV-1 RNA viral load. More information on this criterion can be found in the protocol.
• Ability to take oral medications. NOTE: Administration of fluconazole tablets via nasogastric tube is permitted.
• For patients with a co-morbid complication of HIV, including opportunistic infections, reasonable certainty that the site investigator will be able to perform CSF sampling and manage expected study drug toxicities. More information on this criterion can be found in the protocol.
• For female participants of reproductive potential (defined as girls who have reached menarche or women who have not been post-menopausal for at least 24 consecutive months \[i.e., who have had menses within the preceding 24 months, or have not undergone surgical sterilization, for example, a hysterectomy, or bilateral oophorectomy or salpingotomy\]) a negative serum or urine pregnancy test result must be obtained within 2 days prior to study entry
• All participants must agree not to participate in the conception process (e.g., active attempt to become pregnant or to impregnate, sperm donation, in vitro fertilization).
• If participating in sexual activity that could lead to pregnancy, female study participants must agree to the simultaneous use of two forms of contraception (listed in protocol) during sexual activity, and male study participants must agree to use a condom during such sexual activity. This requirement continues while the study participant is on study treatment and for 6 weeks after fluconazole has been discontinued. More information on this criterion can be found in the protocol.
• Study participants who are not of reproductive potential (defined as women who have been post-menopausal for at least 24 consecutive months, women who have undergone surgical sterilization \[e.g., hysterectomy, or bilateral oophorectomy or salpingectomy\], or men who have documented azoospermia) are eligible without the requirement to use contraceptives. More information on this criterion can be found in the protocol.
• Willingness and ability to adhere to dose schedules and mandatory procedures
• Measured or calculated creatinine clearance of 50 mL/min or more within 3 days prior to study entry. More information on this criterion can be found in the protocol.
• The following laboratory values within 3 days prior to study entry: aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase less than or equal to 5 times the upper limit of normal (ULN); total bilirubin less than or equal to 2.5 times ULN; absolute neutrophil count (ANC) equal to or greater than 750/mm\^3; platelet count equal to or greater than 50,000/mm\^3; hemoglobin equal to or greater than 7.0 g/dL
• Ability and willingness of the participant or legal guardian/representative to give informed consent
• Availability at the site for at least 2 weeks of its standard-of-care ampho B-based regimen

You may not qualify if:

• Expected survival of 2 weeks or less, in the opinion of the site investigator and, if available, the primary care provider
• For patients with a comorbid complication of HIV, anticipated difficulty, in the opinion of the site investigator, in judging response to study treatment as a result of the comorbid complication or the drugs used to treat it
• Breastfeeding
• A prior episode of CM, either as indicated by patient or as noted in patient medical records
• Use of certain drugs within specified time periods. More information on this criterion can be found in the study protocol.
• For candidates who are currently taking nevirapine, the inability to discontinue nevirapine and replace it with a drug that does not have fluconazole drug interactions at or by study entry in the event they are randomized to a high-dose fluconazole treatment arm. More information on this criterion can be found in the study protocol.
• Known allergy, sensitivity to, or intolerance of fluconazole or other imidazole or triazole compounds or to ampho B or other components of the standard of care ampho B based regimen
• History of clinically significant cardiac disease, in the opinion of the site investigator, including symptoms of ischemia, coronary artery disease, congestive heart failure, or arrhythmia
• ECG with QTc interval greater than 450 msec within 7 days prior to study entry. More information on this criterion can be found in the study protocol.
• History of CNS disorder (excluding mood disorders) or concurrent CNS disorder(s) that, in the opinion of the investigator, would interfere with assessment of efficacy (e.g., ability to perform CSF sampling) such as lymphoma, neurocysticercosis, or toxoplasmosis
• Receipt of investigational drug therapy within 30 days prior to study entry without prior approval of the A5225/HiFLAC core team
• Active drug or alcohol use, dependence, or other conditions that in the opinion of the site investigator would jeopardize the safety of a participant in the study or would render the person unable to comply with the study plan
• Randomization to an ampho B-based regimen in Step 1
• Receipt of at least one dose of ampho B-based regimen in Step 1
• Premature discontinuation of ampho B in response to the occurrence of any treatment-limiting toxicity, as described in Section 5 of the A5225/HiFLAC manual of operations (MOPS)

Sponsors & Collaborators

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

Study Sites (10)

University of Southern California CRS

Los Angeles, California, 90033-1079, United States

Location

Byramjee Jeejeebhoy Medical College (BJMC) CRS

Pune, Maharashtra, 411001, India

Location

Kenya Medical Research Institute/Walter Reed Project Clinical Research Center (KEMRI/WRP) CRS

Kericho, Rift Valley, 20200, Kenya

Location

Moi University Clinical Research Center (MUCRC) CRS

Eldoret, 30100, Kenya

Location

San Miguel CRS

Lima, 32, Peru

Location

Wits Helen Joseph Hospital CRS (Wits HJH CRS)

Johannesburg, Gauteng, 2092, South Africa

Location

Durban International Clinical Research Site CRS

Durban, KwaZulu-Natal, 4013, South Africa

Location

Chiang Mai University HIV Treatment (CMU HIV Treatment) CRS

Chiang Mai, 50200, Thailand

Location

Joint Clinical Research Centre (JCRC)/Kampala Clinical Research Site

Kampala, Uganda

Location

Parirenyatwa CRS

Harare, Zimbabwe

Location

Related Publications (4)

• Bicanic T, Meintjes G, Rebe K, Williams A, Loyse A, Wood R, Hayes M, Jaffar S, Harrison T. Immune reconstitution inflammatory syndrome in HIV-associated cryptococcal meningitis: a prospective study. J Acquir Immune Defic Syndr. 2009 Jun 1;51(2):130-4. doi: 10.1097/QAI.0b013e3181a56f2e.

  PMID: 19365271 BACKGROUND

• Pappalardo MC, Szeszs MW, Martins MA, Baceti LB, Bonfietti LX, Purisco SU, Baez AA, Melhem MS. Susceptibility of clinical isolates of Cryptococcus neoformans to amphotericin B using time-kill methodology. Diagn Microbiol Infect Dis. 2009 Jun;64(2):146-51. doi: 10.1016/j.diagmicrobio.2009.02.007. Epub 2009 Apr 2.

  PMID: 19345042 BACKGROUND

• Seddon J, Mangeya N, Miller RF, Corbett EL, Ferrand RA. Recurrence of cryptococcal meningitis in HIV-infected patients following immune reconstitution. Int J STD AIDS. 2009 Apr;20(4):274-5. doi: 10.1258/ijsa.2008.008312.

  PMID: 19304977 BACKGROUND

• Lalloo UG, Komarow L, Aberg JA, Clifford DB, Hogg E, McKhann A, Bukuru A, Lagat D, Pillay S, Mave V, Supparatpinyo K, Samaneka W, Langat D, Ticona E, Badal-Faesen S, Larsen RA; ACTG A5225 Team. Higher Dose Oral Fluconazole for the Treatment of AIDS-related Cryptococcal Meningitis (HIFLAC)-report of A5225, a multicentre, phase I/II, two-stage, dose-finding, safety, tolerability and efficacy randomised, amphotericin B-controlled trial of the AIDS Clinical Trials Group. PLoS One. 2023 Feb 13;18(2):e0281580. doi: 10.1371/journal.pone.0281580. eCollection 2023.

  PMID: 36780493 DERIVED

Related Links

• DAIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (DAIDS AE Grading Table), Version 1.0, December 2004; Clarification, August 2009
• Manual for Expedited Reporting of Adverse Events to DAIDS (DAIDS EAE Manual), Version 2.0, January 2010

MeSH Terms

Conditions

Meningitis, Cryptococcal; HIV Infections; Meningitis

Interventions

Fluconazole; Amphotericin B; amphotericin B, deoxycholate drug combination; liposomal amphotericin B

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; 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)

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

Results Point of Contact

• Title: ACTG Clinicaltrials.gov Coordinator
• Organization: ACTG Network Coordinating Center, Social and Scientific Systems, Inc.

ACTGCT.Gov@s-3.com

(301) 628-3313

Study Officials

• Umesh G. Lalloo, MD, FRCP

  Nelson R. Mandela School of Medicine

  STUDY CHAIR

• Robert A. Larsen, MD

  USC School of Medicine

  STUDY CHAIR

Publication Agreements

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

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Model Details: Phase 1 was the dose escalation phase which used a sequential model. Phase 2 was the dose validation phase which used a parallel model. Analyses combine arms from Phase 1 and Phase 2, as appropriate, for validation.

Study Record Dates

• First Submitted: April 20, 2009
• First Posted: April 22, 2009
• Study Start: April 16, 2010
• Primary Completion: January 12, 2017
• Study Completion: January 12, 2017
• Last Updated: November 4, 2021
• Results First Posted: March 12, 2018

Record last verified: 2018-02

Locations

PE (1); KE (2); US (1); ZA (2); ZI (1); UG (1); IN (1); TH (1)