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

• Register: ClinicalTrials.gov
• Last refreshed on: 15 November 2021
• Main ID: NCT00885703
• Date of registration: 20/04/2009
• Prospective Registration: Yes
• Primary sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
• Public title: High-Dose Fluconazole for the Treatment of Cryptococcal Meningitis in HIV-Infected Individuals
• Scientific title: A Phase I/II Dose-Finding Study of High-Dose Fluconazole Treatment in AIDS-Associated Cryptococcal Meningitis
• Date of first enrolment: April 16, 2010
• Target sample size: 168
• Recruitment status: Completed
• URL: https://clinicaltrials.gov/show/NCT00885703
• Study type: Interventional
• Study design: Allocation: Randomized. Intervention model: Parallel Assignment. Primary purpose: Treatment. Masking: None (Open Label).
• Phase: Phase 1/Phase 2

Countries of recruitment

India, Kenya, Peru, South Africa, Thailand, Uganda, United States, Zimbabwe

Contacts

• Name: Robert A. Larsen, MD
• Affiliation: USC School of Medicine

• Name: Umesh G. Lalloo, MD, FRCP
• Affiliation: Nelson R. Mandela School of Medicine

Key inclusion & exclusion criteria

Inclusion Criteria - Step 1

- 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

Exclusion Criteria - Step 1

- 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

Inclusion Criteria - Step 2

- 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)

Exclusion Criteria - Step 2

- Receipt of fluconazole monotherapy in Step 1

- Receipt of 8.4 mg/kg or more of ampho B

- At or beyond Day 17 in Step 1

Inclusion Criteria - Step 3

-


Age minimum: 16 Years
Age maximum: N/A
Gender: All

Health Condition(s) or Problem(s) studied

Cryptococcal Meningitis

HIV Infections

Intervention(s)

Drug: Amphotericin B

Drug: Fluconazole

Primary Outcome(s)

Categorized Quantitative Culture Results [Time Frame: At entry, Week 2, and Week 10]

Number of Participants Who Discontinued Study-provided High Dose Fluconazole or Ampho B [Time Frame: Measured from study entry through Week10]

Kaplan Meier (KM) Proportion of Participant Mortality [Time Frame: Measured from study entry through Week 24]

Change in Log10 Quantitative CSF Culture Results [Time Frame: Entry and Week 2]

Secondary Outcome(s)

Number of Participants With CNS IRIS [Time Frame: Measured from study entry through Week 24]

Length of Hospitalization [Time Frame: Measured from study entry through Week 10]

Number of Participants With Grade 3 and 4 Adverse Events [Time Frame: Measured from study entry through Week 24]

Number of Hospital Admissions [Time Frame: Measured from study entry through Week 24]

Results of the Neurological Examination [Time Frame: Measured at study entry, Week 2, and Week 10]

Number of Participants With Progression of Symptoms [Time Frame: Measured from study entry through Week 24]

Results of Functional Status Evaluation [Time Frame: Measured 6 weeks before enrollment, at study entry, at Week 10, and at Week 24]

Secondary ID(s)

A5225/HiFLAC

A5225 (HiFLAC)

ACTG A5225

10149

A5225

HiFLAC

Source(s) of Monetary Support

Please refer to primary and secondary sponsors

Results

• Results available: Yes
• Date Posted: 12/03/2018
• URL: https://clinicaltrials.gov/ct2/show/results/NCT00885703