HIV Infections Clinical Trial
Official title:
A Phase I/II Dose-Finding Study of High-Dose Fluconazole Treatment in AIDS-Associated Cryptococcal Meningitis
Verified date | February 2018 |
Source | National Institute of Allergy and Infectious Diseases (NIAID) |
Contact | n/a |
Is FDA regulated | No |
Health authority | |
Study type | Interventional |
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.
Status | Completed |
Enrollment | 168 |
Est. completion date | January 12, 2017 |
Est. primary completion date | January 12, 2017 |
Accepts healthy volunteers | No |
Gender | All |
Age group | 16 Years and older |
Eligibility | 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 - For participants in Step 1 who are currently receiving study-provided fluconazole and have no plans to discontinue study treatment (except as noted below), a negative CSF culture after 2 weeks incubation from a sample obtained at or before Week 6 (Days 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. More information on this criterion can be found in the study protocol. - For participants in Step 2 who are currently receiving study-provided fluconazole and have no plans to discontinue study treatment, negative CSF culture after 2 weeks incubation from a sample obtained at or before Week 6 (Days 35-49). Exclusion Criteria - Step 3 - On study treatment beyond Week 10 (Day 77) in Step 1 or Step 2 - Currently off study treatment Inclusion Criteria - Step 4 - On study treatment at Week 10 (Days 63-77) with no plans to discontinue study treatment Exclusion Criteria - Step 4 - Currently off study treatment |
Country | Name | City | State |
---|---|---|---|
India | Byramjee Jeejeebhoy Medical College (BJMC) CRS | Pune | Maharashtra |
Kenya | Moi University Clinical Research Center (MUCRC) CRS | Eldoret | |
Kenya | Kenya Medical Research Institute/Walter Reed Project Clinical Research Center (KEMRI/WRP) CRS | Kericho | Rift Valley |
Peru | San Miguel CRS | Lima | |
South Africa | Durban International Clinical Research Site CRS | Durban | KwaZulu-Natal |
South Africa | Wits Helen Joseph Hospital CRS (Wits HJH CRS) | Johannesburg | Gauteng |
Thailand | Chiang Mai University HIV Treatment (CMU HIV Treatment) CRS | Chiang Mai | |
Uganda | Joint Clinical Research Centre (JCRC)/Kampala Clinical Research Site | Kampala | |
United States | University of Southern California CRS | Los Angeles | California |
Zimbabwe | Parirenyatwa CRS | Harare |
Lead Sponsor | Collaborator |
---|---|
National Institute of Allergy and Infectious Diseases (NIAID) |
United States, Zimbabwe, India, Kenya, Peru, South Africa, Thailand, Uganda,
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. — View Citation
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. — View Citation
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. — View Citation
Type | Measure | Description | Time frame | Safety issue |
---|---|---|---|---|
Primary | 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 | |
Primary | 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 | |
Primary | 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 | |
Primary | 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 | Results of the Neurological Examination | Results from Glasgow Coma Score, which provides assessment of impairment of conscious level in response to defined stimuli. Min score of 0 and max score of 15 (no mental impairment). | Measured at study entry, Week 2, and Week 10 | |
Secondary | Results of Functional Status Evaluation | Functional assessment of work status and ability. Consists of 2 measures: 1) Does participants have full time work status 2) Does participant have functional ability to work. The measure from 6 week before enrollment will be referred to as 'baseline'. |
Measured 6 weeks before enrollment, at study entry, at Week 10, and at Week 24 | |
Secondary | Length of Hospitalization | Duration of first hospitalization in days starting at entry in safety population. | Measured from study entry through Week 10 | |
Secondary | Number of Hospital Admissions | Count of number of times a participant was admitted to the hospital. | Measured from study entry through Week 24 | |
Secondary | Number of Participants With Progression of Symptoms | Progression of symptoms is defined as: Died (including early deaths) Discontinued Fluconazole and started ampho B Had a positive cryptococcal culture at week 10 Microbiological Failure (i.e., relapse of CM) Complication of CM (e.g., obstructive hydrocephalus or vascular complications such as venous or arterial thrombosis) CM IRIS causing increased inflammation after ART exposure New CNS Ol (e.g., toxoplasmosis, PML, CNS lymphoma) Possibly related to CM but mechanism indeterminate Other defined complication unrelated to CM |
Measured from study entry through Week 24 | |
Secondary | Number of Participants With CNS IRIS | Number of participants who were diagnosed with CNS immune reconstitution inflammatory syndrome (IRIS) | Measured from study entry through Week 24 | |
Secondary | Number of Participants With Grade 3 and 4 Adverse Events | Occurrence of grade 3 (severe) and 4 (life-threatening) sign and symptoms events (as defined by FSTRF Appendix 29) Occurrence of grade 3 (severe) and 4 (life-threatening) laboratory events (as defined by FSTRF Appendix 76) See DAIDS AE Grading table V1.0 |
Measured from study entry through Week 24 |
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