| City: |
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Los Angeles |
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State:
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CA |
| Zip Code: |
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90033 |
| Conditions: |
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Cryptococcal Meningitis - HIV Infections |
| Purpose: |
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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 will explore
the safety, tolerability, and therapeutic effect of a new treatment regimen with high-dose
fluconazole for management of CM in HIV-infected patients.
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| Study summary: |
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Cryptococcal meningitis (CM) is the most common central nervous system (CNS) complication of
AIDS worldwide and accounts for up to a third of all deaths from AIDS in many developing
countries. Current treatments for CM are lacking in both effectiveness and accessibility,
particularly in limited-resources settings. Conventional therapies utilizing an amphotericin
B deoxycholate (ampho B)-based regimen require maintaining intravenous access (IV), and
monitoring and treating any associated complications. The price to acquire ampho B can also
be prohibitive to successful treatment. Cumulatively, a treatment course with ampho B is
neither cost-effective nor administratively efficient, leaving patients either untreated or
inadequately treated with low-dose regimens of fluconazole alone.
Fluconazole is widely available, inexpensive, can be given orally, has a demonstrated safety
profile over a broad range of doses, and has proven activity against the fungus which causes
CM, Cryptococcus neoforman. All of these factors, make fluconazole a potential treatment
option for a wide range of people. However, at its present recommended dosage, fluconazole
is only expected to be successful in 34 to 42% of patients. This rate is lower than regimens
combining fluconazole with other treatments including, flucytosine or ampho B. This study
will evaluate fluconazole administered alone and at doses of 1200, 1600, and/or 2000 mg/day
will be well tolerated in and safe for patients for the treatment of CM.
For this study, up to 192 HIV-infected people with CM will participate for duration of 24
weeks. This study will proceed in two stages. Each stage may consist of up to four steps.
Stage 1 will be measuring for the maximum tolerated dose (MTD) of fluconazole in patients,
and can last a maximum of 24 weeks. Stage 2 will be for the purpose of dose validation.
Participants will take part in only one stage of the study. If enrolled for Stage 1,
participants will be randomly assigned to receive either fluconazole only or ampho B
followed by fluconazole treatment. There will be three possible fluconazole doses available
for the start of the fluconazole-only treatment. The dosage will depend on when a
participant enters the study.
Participants in Stage 2 will also be randomly assigned to either receive treatment with
fluconazole only or ampho-B followed by fluconazole.
Participants in Stage 2 receiving fluconazole only will start with a dose of either 1200 mg
daily, 1600 mg daily, or 2000 milligrams daily, depending on the MTD determined in Stage 1.
After 10 weeks on study, dosage will be reduced to 400 mg daily (Step 3) and subsequently to
200 mg daily (Step 4), until the end of the study.
Participants in both Stages beginning treatment with ampho B will receive their medication
daily for about 2 weeks. Administration of ampho B will take approximately 1 hour.
Flucytosine may also be given in combination with ampho B. After about 2 weeks of receiving
ampho B, participant will be given fluconazole until the end of the study, with a dose
reduction after 10 weeks.
Before entering the study, potential participants will attend a screening visit where they
will have their CM diagnosis confirmed with spinal fluid collected via lumbar puncture. HIV
testing will also be conducted, along with a physical examination, health and medical
history questionnaire. Participants will also have blood drawn, an electrocardiogram (ECG),
and a pregnancy test (if applicable). Once accepted into the study, participants will again
answer questions about their health and medication history, have a physical exam, blood
drawn, HIV testing, neurological exam, lumbar puncture, and may have a pregnancy test (if
applicable). Participants will have study visits during Weeks 1, 2, 4, 6, 8, 10, and 24.
Participants receiving treatment with ampho B may have a few more study visits than other
participants. Total study duration will be 6 months. |
| Criteria: |
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Inclusion Criteria - Step 1
- Cryptococcal meningitis 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
- 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 a licensed Western blot or a second antibody test by a method other than
the initial rapid HIV and/or E/CIA, or by HIV-1 antigen, plasma HIV-1 RNA viral load
- Ability to take oral medications.
- For patients with a co-morbid complication of HIV, including opportunistic
infections, receipt of stable treatment for the co-morbid complication and clinically
stable, as judged by the site investigator
- For female participants of reproductive potential a negative serum or urine pregnancy
test result must be obtained within 3 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, participants must
use a form of contraceptive listed below while on study treatment and for 6 weeks
after has been discontinued
- 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
- Required laboratory values within 3 days prior to study entry. More information on
this criterion can be found in the study protocol
- Ability and willingness of the participant or legal guardian/representative to give
informed consent
- Availability at the site of 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
- For patients with a co-morbid complication of HIV, anticipated difficulty, in the
opinion of the site investigator, in judging response to study treatment as a result
of the co-morbid complication or the drugs used to treat it
- 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.
- Suspected or active tuberculosis (TB), even if untreated, for participants screening
at the time that a 1200 mg daily fluconazole induction cohort is enrolling
- 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 opinion of site investigator,
including symptoms of ischemia, coronary artery disease, congestive heart failure, or
arrhythmia
- ECG (electrocardiogram) with QTc interval greater than 450 msec within 7 days prior
to study entry.
- 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
- Receipt of specified treatments for the current episode of CM. More information on
this criterion can be found in the study protocol.
- 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
- Breast-feeding
Inclusion Criterion - 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 MOPS
Exclusion Criterion - 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
- For participants in Step 1 who are currently receiving study-provided fluconazole, a
negative CSF culture after 2 weeks incubation from a sample obtained at or before
week 6 (day 35-49)
- For participants in Step 1 who are currently receiving an ampho B-based regimen or
alternative treatment, completion of approximately 2 weeks of treatment
- For participants in Step 2 who are currently receiving study-provided fluconazole,
negative CSF culture after 2 weeks incubation from a sample obtained at or before
week 6 (day 35-49).
Exclusion Criteria - Step 3
- On study treatment beyond week 10 (day 77) in Step 1 or Step 2
Inclusion Criteria - Step 4
- On study treatment at week 10 (day 63-77)
Exclusion Criteria - Step 4
- None |
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| Study is available at: |
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Usc Crs
Los Angeles, CA 90033
United States
Primary Contact:
Luis M. Mendez
Email: lmendez@usc.edu
Phone: 323-343-8288 |
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If you are interested in this clinical trial please use the contact information above. If you would like to get additional information about this clinical trial please visit ClinicalTrials.gov.
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| Data Source: |
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ClinicalTrials.gov |
| Date Processed: |
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March 23, 2011 |
Modifications to
this listing: |
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Only selected fields are shown, please use the link
above to view all information about this clinical trial. |
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