Cryptococcal Meningitis
Conditions
Keywords
Bacterial infections, HIV infection, cryptococcal meningitis
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.
Detailed description
This study is designed to address the need for more effective antifungal therapy for cryptococcal meningitis. This is a prospective, randomized, open-label, multicenter phase II clinical trial of combination therapy for the treatment of acute cryptococcal meningitis in HIV-positive subjects. The primary study objectives will be to assess the safety and tolerability of the study drug regimens; and to determine whether the safety and efficacy of combination therapy supports development of a phase III trial of combination therapy, and if so, to select the most appropriate dose of fluconazole plus amphotericin B based on safety and efficacy to be evaluated in a subsequent phase III trial. Secondary study objectives include: comparing the efficacy of the study drug treatments at 2, 6, and 10 weeks (Days 14, 42, and 70); comparing the findings on detailed neurological examination between study arms at baseline and 2, 6, 10, and 24 weeks (6 months); assessing the proportion of subjects in each study arm that are alive at 6 months after initiation of study therapy; describing the effects of baseline clinical, neurological, and mycological characteristics on mycological failure at 2 and 10 weeks; measuring time to cerebrospinal fluid (CSF) culture negatively for each study arm; assessing the length of hospitalization in the treatment groups as a surrogate of cost efficacy; assessing the incidence of immune reconstitution inflammatory syndrome among all subjects receiving highly active antiretroviral therapy (HAART); and examining antifungal susceptibility of all cryptococcal isolates. Study participants will include 150 subjects ages 13 and older. Subjects will be randomly assigned to 1 of 3 treatment arms including 1 standard therapy and 2 investigational arms. The standard treatment arm will include amphotericin B 0.7 mg/kg (IV) for 14 days followed by 8 weeks (56 days) of fluconazole at 400 mg/day orally. The 2 investigational arms will include daily amphotericin B 0.7 mg/kg (IV) and the randomized dose of fluconazole 400 mg/day or 800 mg/day for the first 14 day, then the randomized dose of fluconazole at 400 mg/day or 800 mg/day respectively for an additional 8 weeks (56 days). At the completion of study therapy, all subjects will receive chronic suppressive therapy with oral fluconazole at a dose of at least 200 mg/day. The safety endpoints are considered to be the primary endpoints for this study. The safety assessment for each treatment arm will end at study day 100 for each subject. The key safety endpoint will be the incidence of adverse experiences of grade 3-5 (total and attributed to the treatment regimens). The primary safety endpoint will examine the incidence of grade 3-5 adverse experiences that are definitely or probably related to study drugs, while secondary analysis will include grade 3-5 adverse experiences that are, definitely probably or possibly related to study drugs. Another secondary safety endpoint will be the number of dose-limiting toxicities attributed to the treatment regimens. Key efficacy endpoint (treatment success) will be a composite of the following 3 mycologic and clinical measures after 14, 42, and 70 days of therapy: CSF culture conversion; neurologically stable or improved; and alive. Other secondary efficacy endpoints that will be evaluated descriptively are: CSF culture conversion at multiple time points; all-cause mortality; length of hospitalization; and incidence of immune reconstitution inflammatory syndrome.
Interventions
DRUGAmphotericin B
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.
DRUGFluconazole
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.
Sponsors
National Institute of Allergy and Infectious Diseases (NIAID)
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
13 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* 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. OR -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. OR * 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.
Exclusion criteria
* 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.) * Previous participation in this study or ongoing participation in another trial with an investigational drug. * Prior case of cryptococcosis with diagnosed central nervous system involvement.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Grade 3-5 Adverse Experiences That Are Definitely or Probably Related to Study Drug | Day 100 | 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. |
| Number of Dose-limiting Toxicities Attributed to Treatment Regimens | Day 100 | Events are reported by MedDRA Preferred Term. Dose limiting toxicities include events that resulted in study drug being adjusted, interrupted, or discontinued. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Subjects Meeting the Key Efficacy Endpoint of Treatment Success | 14, 42, and 70 days | Treatment success is defined as a composite of the 3 mycologic and clinical measures: CSF culture conversion; neurologically stable or improved; and alive |
| Number of Subjects Reporting Immune Reconstitution Inflammatory Syndrome (IRIS) | 14, 42, and 70 days | Number of subjects reporting immune reconstitution inflammatory syndrome (IRIS) following treatment. Day = Day relative to first dose of study drug |
| Mean Days of Hospitalization | 7, 14, 42, and 70 days | Mean days of hospitalization. Includes days subject was hospitalized prior to study enrollment for current hospital stay. |
| Number of Cryptococcal Isolates With Antifungal Susceptibility | Days 14 and 70 | Isolates were collected at days 14 and 70 for assessment of antifungal susceptibility. |
| Number of Deaths | 14, 42, and 70 days | Number of deaths occurring on study. Day = Day relative to the first dose of study drug. |
| Mean Change in Neurological Exam Score From Baseline - Day 42 | Baseline and Day 42 | Neurological assessment by Mini-mental Status Exam (MMSE). This is collected as a continuous variable with values from 0-30; where lower scores indicate greater impairment. |
| Mean Change in Neurological Exam Score From Baseline - Day 70 | Baseline and Day 70 | Neurological assessment by Mini-mental Status Exam (MMSE). This is collected as a continuous variable with values from 0-30; where lower scores indicate greater impairment. |
| Mean Change in Neurological Exam Score From Baseline - Day 168 | Baseline and Day 168 | Neurological assessment by Mini-mental Status Exam (MMSE). This is collected as a continuous variable with values from 0-30; where lower scores indicate greater impairment. |
| Mean Change in Neurological Exam Score From Baseline - Day 14 | Baseline and Day 14 | Neurological assessment by Mini-mental Status Exam (MMSE). This is collected as a continuous variable with values from 0-30; where lower scores indicate greater impairment. |
| Number of Subjects With Cerebrospinal Fluid (CSF) Culture Conversion at Multiple Time Points | Baseline, 14, 42, and 70 days | Number of subjects that have a negative fungal culture at Baseline, Day 14, Day 42, and Day 70. |
Countries
Thailand, United States
Participant flow
Recruitment details
Subjects were screened and enrolled at 10 sites in the US and 5 sites in Thailand.
Participants by arm
| Arm | Count |
|---|---|
| AmphoB Standard 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. | 45 |
| AmphoB+Fluc400 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. | 47 |
| AmphoB + Fluc800 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. | 49 |
| Total | 141 |
Baseline characteristics
| Characteristic | AmphoB Standard | AmphoB+Fluc400 | AmphoB + Fluc800 | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Age, Categorical Between 18 and 65 years | 45 Participants | 47 Participants | 47 Participants | 139 Participants |
| Age Continuous | 37.1 years STANDARD_DEVIATION 8.47 | 36.5 years STANDARD_DEVIATION 8.21 | 35.9 years STANDARD_DEVIATION 9.44 | 36.5 years STANDARD_DEVIATION 8.69 |
| Region of Enrollment Thailand | 31 participants | 33 participants | 35 participants | 99 participants |
| Region of Enrollment United States | 14 participants | 14 participants | 14 participants | 42 participants |
| Sex: Female, Male Female | 16 Participants | 15 Participants | 18 Participants | 49 Participants |
| Sex: Female, Male Male | 29 Participants | 32 Participants | 31 Participants | 92 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 44 / 45 | 47 / 47 | 49 / 49 |
| serious Total, serious adverse events | 22 / 45 | 17 / 47 | 26 / 49 |
Outcome results
Primary
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.
Time frame: Day 100
Population: The Regulatory Safety population includes all subjects who were randomized, who receive at least 1 dose of study drug, and who have any on-study data.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| AmphoB Standard | Number of Dose-limiting Toxicities Attributed to Treatment Regimens | Chills | 0 Events |
| AmphoB Standard | Number of Dose-limiting Toxicities Attributed to Treatment Regimens | Azotaemia | 0 Events |
| AmphoB Standard | Number of Dose-limiting Toxicities Attributed to Treatment Regimens | Blood creatinine increased | 4 Events |
| AmphoB Standard | Number of Dose-limiting Toxicities Attributed to Treatment Regimens | All Events | 6 Events |
| AmphoB Standard | Number of Dose-limiting Toxicities Attributed to Treatment Regimens | Renal impairment | 0 Events |
| AmphoB Standard | Number of Dose-limiting Toxicities Attributed to Treatment Regimens | Hepatitis acute | 1 Events |
| AmphoB Standard | Number of Dose-limiting Toxicities Attributed to Treatment Regimens | Drug intolerance | 1 Events |
| AmphoB Standard | Number of Dose-limiting Toxicities Attributed to Treatment Regimens | Nausea | 0 Events |
| AmphoB Standard | Number of Dose-limiting Toxicities Attributed to Treatment Regimens | Creatinine renal clearance increased | 0 Events |
| AmphoB Standard | Number of Dose-limiting Toxicities Attributed to Treatment Regimens | Vomiting | 0 Events |
| AmphoB Standard | Number of Dose-limiting Toxicities Attributed to Treatment Regimens | Respiratory failure | 0 Events |
| AmphoB Standard | Number of Dose-limiting Toxicities Attributed to Treatment Regimens | Pneumonia | 0 Events |
| AmphoB Standard | Number of Dose-limiting Toxicities Attributed to Treatment Regimens | Renal failure | 0 Events |
| AmphoB Standard | Number of Dose-limiting Toxicities Attributed to Treatment Regimens | Dehydration | 0 Events |
| AmphoB Standard | Number of Dose-limiting Toxicities Attributed to Treatment Regimens | Neutropenia | 0 Events |
| AmphoB Standard | Number of Dose-limiting Toxicities Attributed to Treatment Regimens | Renal failure acute | 0 Events |
| AmphoB Standard | Number of Dose-limiting Toxicities Attributed to Treatment Regimens | Creatinine renal clearance decreased | 0 Events |
| AmphoB+Fluc400 | Number of Dose-limiting Toxicities Attributed to Treatment Regimens | Drug intolerance | 1 Events |
| AmphoB+Fluc400 | Number of Dose-limiting Toxicities Attributed to Treatment Regimens | All Events | 7 Events |
| AmphoB+Fluc400 | Number of Dose-limiting Toxicities Attributed to Treatment Regimens | Blood creatinine increased | 1 Events |
| AmphoB+Fluc400 | Number of Dose-limiting Toxicities Attributed to Treatment Regimens | Creatinine renal clearance decreased | 1 Events |
| AmphoB+Fluc400 | Number of Dose-limiting Toxicities Attributed to Treatment Regimens | Creatinine renal clearance increased | 0 Events |
| AmphoB+Fluc400 | Number of Dose-limiting Toxicities Attributed to Treatment Regimens | Renal failure | 2 Events |
| AmphoB+Fluc400 | Number of Dose-limiting Toxicities Attributed to Treatment Regimens | Renal failure acute | 1 Events |
| AmphoB+Fluc400 | Number of Dose-limiting Toxicities Attributed to Treatment Regimens | Azotaemia | 0 Events |
| AmphoB+Fluc400 | Number of Dose-limiting Toxicities Attributed to Treatment Regimens | Renal impairment | 0 Events |
| AmphoB+Fluc400 | Number of Dose-limiting Toxicities Attributed to Treatment Regimens | Nausea | 0 Events |
| AmphoB+Fluc400 | Number of Dose-limiting Toxicities Attributed to Treatment Regimens | Vomiting | 0 Events |
| AmphoB+Fluc400 | Number of Dose-limiting Toxicities Attributed to Treatment Regimens | Chills | 1 Events |
| AmphoB+Fluc400 | Number of Dose-limiting Toxicities Attributed to Treatment Regimens | Neutropenia | 0 Events |
| AmphoB+Fluc400 | Number of Dose-limiting Toxicities Attributed to Treatment Regimens | Hepatitis acute | 0 Events |
| AmphoB+Fluc400 | Number of Dose-limiting Toxicities Attributed to Treatment Regimens | Pneumonia | 0 Events |
| AmphoB+Fluc400 | Number of Dose-limiting Toxicities Attributed to Treatment Regimens | Dehydration | 0 Events |
| AmphoB+Fluc400 | Number of Dose-limiting Toxicities Attributed to Treatment Regimens | Respiratory failure | 0 Events |
| AmphoB + Fluc800 | Number of Dose-limiting Toxicities Attributed to Treatment Regimens | Blood creatinine increased | 1 Events |
| AmphoB + Fluc800 | Number of Dose-limiting Toxicities Attributed to Treatment Regimens | Chills | 0 Events |
| AmphoB + Fluc800 | Number of Dose-limiting Toxicities Attributed to Treatment Regimens | Renal failure | 0 Events |
| AmphoB + Fluc800 | Number of Dose-limiting Toxicities Attributed to Treatment Regimens | Respiratory failure | 1 Events |
| AmphoB + Fluc800 | Number of Dose-limiting Toxicities Attributed to Treatment Regimens | Neutropenia | 1 Events |
| AmphoB + Fluc800 | Number of Dose-limiting Toxicities Attributed to Treatment Regimens | Hepatitis acute | 0 Events |
| AmphoB + Fluc800 | Number of Dose-limiting Toxicities Attributed to Treatment Regimens | Creatinine renal clearance increased | 2 Events |
| AmphoB + Fluc800 | Number of Dose-limiting Toxicities Attributed to Treatment Regimens | Creatinine renal clearance decreased | 2 Events |
| AmphoB + Fluc800 | Number of Dose-limiting Toxicities Attributed to Treatment Regimens | Dehydration | 1 Events |
| AmphoB + Fluc800 | Number of Dose-limiting Toxicities Attributed to Treatment Regimens | All Events | 14 Events |
| AmphoB + Fluc800 | Number of Dose-limiting Toxicities Attributed to Treatment Regimens | Nausea | 1 Events |
| AmphoB + Fluc800 | Number of Dose-limiting Toxicities Attributed to Treatment Regimens | Pneumonia | 1 Events |
| AmphoB + Fluc800 | Number of Dose-limiting Toxicities Attributed to Treatment Regimens | Vomiting | 1 Events |
| AmphoB + Fluc800 | Number of Dose-limiting Toxicities Attributed to Treatment Regimens | Renal impairment | 1 Events |
| AmphoB + Fluc800 | Number of Dose-limiting Toxicities Attributed to Treatment Regimens | Azotaemia | 1 Events |
| AmphoB + Fluc800 | Number of Dose-limiting Toxicities Attributed to Treatment Regimens | Drug intolerance | 0 Events |
| AmphoB + Fluc800 | Number of Dose-limiting Toxicities Attributed to Treatment Regimens | Renal failure acute | 1 Events |
Primary
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.
Time frame: Day 100
Population: The Regulatory Safety population includes all subjects who were randomized, who receive at least 1 dose of study drug, and who have any on-study data.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| AmphoB Standard | Number of Grade 3-5 Adverse Experiences That Are Definitely or Probably Related to Study Drug | Hypomagnesaemia | 2 Events |
| AmphoB Standard | Number of Grade 3-5 Adverse Experiences That Are Definitely or Probably Related to Study Drug | Hypokalaemia | 0 Events |
| AmphoB Standard | Number of Grade 3-5 Adverse Experiences That Are Definitely or Probably Related to Study Drug | Anaemia | 1 Events |
| AmphoB Standard | Number of Grade 3-5 Adverse Experiences That Are Definitely or Probably Related to Study Drug | Drug intolerance | 1 Events |
| AmphoB Standard | Number of Grade 3-5 Adverse Experiences That Are Definitely or Probably Related to Study Drug | Creatinine renal clearance increased | 0 Events |
| AmphoB Standard | Number of Grade 3-5 Adverse Experiences That Are Definitely or Probably Related to Study Drug | Psychotic disorder | 0 Events |
| AmphoB+Fluc400 | Number of Grade 3-5 Adverse Experiences That Are Definitely or Probably Related to Study Drug | Psychotic disorder | 0 Events |
| AmphoB+Fluc400 | Number of Grade 3-5 Adverse Experiences That Are Definitely or Probably Related to Study Drug | Hypomagnesaemia | 1 Events |
| AmphoB+Fluc400 | Number of Grade 3-5 Adverse Experiences That Are Definitely or Probably Related to Study Drug | Drug intolerance | 0 Events |
| AmphoB+Fluc400 | Number of Grade 3-5 Adverse Experiences That Are Definitely or Probably Related to Study Drug | Creatinine renal clearance increased | 0 Events |
| AmphoB+Fluc400 | Number of Grade 3-5 Adverse Experiences That Are Definitely or Probably Related to Study Drug | Hypokalaemia | 0 Events |
| AmphoB+Fluc400 | Number of Grade 3-5 Adverse Experiences That Are Definitely or Probably Related to Study Drug | Anaemia | 1 Events |
| AmphoB + Fluc800 | Number of Grade 3-5 Adverse Experiences That Are Definitely or Probably Related to Study Drug | Hypokalaemia | 1 Events |
| AmphoB + Fluc800 | Number of Grade 3-5 Adverse Experiences That Are Definitely or Probably Related to Study Drug | Anaemia | 0 Events |
| AmphoB + Fluc800 | Number of Grade 3-5 Adverse Experiences That Are Definitely or Probably Related to Study Drug | Psychotic disorder | 1 Events |
| AmphoB + Fluc800 | Number of Grade 3-5 Adverse Experiences That Are Definitely or Probably Related to Study Drug | Drug intolerance | 0 Events |
| AmphoB + Fluc800 | Number of Grade 3-5 Adverse Experiences That Are Definitely or Probably Related to Study Drug | Hypomagnesaemia | 0 Events |
| AmphoB + Fluc800 | Number of Grade 3-5 Adverse Experiences That Are Definitely or Probably Related to Study Drug | Creatinine renal clearance increased | 1 Events |
Secondary
Mean Change in Neurological Exam Score From Baseline - Day 14
Neurological assessment by Mini-mental Status Exam (MMSE). This is collected as a continuous variable with values from 0-30; where lower scores indicate greater impairment.
Time frame: Baseline and Day 14
Population: The number of subjects tested in the modified Intent to Treat (mITT) population includes all subjects who are randomized to a treatment arm \& receive any dose of study drug, who provide any outcome data, \& who are determined to have met 2 key criteria for inclusion in the primary analysis: diagnosis of cryptococcal meningitis \& HIV infection.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| AmphoB Standard | Mean Change in Neurological Exam Score From Baseline - Day 14 | 0.5 Scores on a scale | Standard Deviation 4.07 |
| AmphoB+Fluc400 | Mean Change in Neurological Exam Score From Baseline - Day 14 | 2.1 Scores on a scale | Standard Deviation 3.74 |
| AmphoB + Fluc800 | Mean Change in Neurological Exam Score From Baseline - Day 14 | 3.5 Scores on a scale | Standard Deviation 6.25 |
Secondary
Mean Change in Neurological Exam Score From Baseline - Day 168
Neurological assessment by Mini-mental Status Exam (MMSE). This is collected as a continuous variable with values from 0-30; where lower scores indicate greater impairment.
Time frame: Baseline and Day 168
Population: The number of subjects tested in the modified Intent to Treat (mITT) population includes all subjects who are randomized to a treatment arm \& receive any dose of study drug, who provide any outcome data, \& who are determined to have met 2 key criteria for inclusion in the primary analysis: diagnosis of cryptococcal meningitis \& HIV infection.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| AmphoB Standard | Mean Change in Neurological Exam Score From Baseline - Day 168 | 2.0 Scores on a scale | Standard Deviation 2.28 |
| AmphoB+Fluc400 | Mean Change in Neurological Exam Score From Baseline - Day 168 | 2.8 Scores on a scale | Standard Deviation 3.92 |
| AmphoB + Fluc800 | Mean Change in Neurological Exam Score From Baseline - Day 168 | 4.4 Scores on a scale | Standard Deviation 7.58 |
Secondary
Mean Change in Neurological Exam Score From Baseline - Day 42
Neurological assessment by Mini-mental Status Exam (MMSE). This is collected as a continuous variable with values from 0-30; where lower scores indicate greater impairment.
Time frame: Baseline and Day 42
Population: The number of subjects tested in the modified Intent to Treat (mITT) population includes all subjects who are randomized to a treatment arm \& receive any dose of study drug, who provide any outcome data, \& who are determined to have met 2 key criteria for inclusion in the primary analysis: diagnosis of cryptococcal meningitis \& HIV infection.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| AmphoB Standard | Mean Change in Neurological Exam Score From Baseline - Day 42 | 1.6 Scores on a scale | Standard Deviation 2.58 |
| AmphoB+Fluc400 | Mean Change in Neurological Exam Score From Baseline - Day 42 | 1.8 Scores on a scale | Standard Deviation 4.42 |
| AmphoB + Fluc800 | Mean Change in Neurological Exam Score From Baseline - Day 42 | 3.3 Scores on a scale | Standard Deviation 7.9 |
Secondary
Mean Change in Neurological Exam Score From Baseline - Day 70
Neurological assessment by Mini-mental Status Exam (MMSE). This is collected as a continuous variable with values from 0-30; where lower scores indicate greater impairment.
Time frame: Baseline and Day 70
Population: The number of subjects tested in the modified Intent to Treat (mITT) population includes all subjects who are randomized to a treatment arm \& receive any dose of study drug, who provide any outcome data, \& who are determined to have met 2 key criteria for inclusion in the primary analysis: diagnosis of cryptococcal meningitis \& HIV infection.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| AmphoB Standard | Mean Change in Neurological Exam Score From Baseline - Day 70 | 1.5 Scores on a scale | Standard Deviation 3.28 |
| AmphoB+Fluc400 | Mean Change in Neurological Exam Score From Baseline - Day 70 | 2.2 Scores on a scale | Standard Deviation 3.58 |
| AmphoB + Fluc800 | Mean Change in Neurological Exam Score From Baseline - Day 70 | 4.2 Scores on a scale | Standard Deviation 6.84 |
Secondary
Mean Days of Hospitalization
Mean days of hospitalization. Includes days subject was hospitalized prior to study enrollment for current hospital stay.
Time frame: 7, 14, 42, and 70 days
Population: The mITT population includes all subjects who are randomized to a treatment arm and receive any dose of study drug, who provide any outcome data, and who are determined to have met 2 key criteria for inclusion in the primary analysis - diagnosis of culture-proven cryptococcal meningitis and proven HIV infection.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| AmphoB Standard | Mean Days of Hospitalization | Day 70 | 16.7 Days | Standard Deviation 4.54 |
| AmphoB Standard | Mean Days of Hospitalization | Day 42 | 16.3 Days | Standard Deviation 4.22 |
| AmphoB Standard | Mean Days of Hospitalization | Day 14 | 15.4 Days | Standard Deviation 1.78 |
| AmphoB Standard | Mean Days of Hospitalization | Day 7 | 8.9 Days | Standard Deviation 1.61 |
| AmphoB+Fluc400 | Mean Days of Hospitalization | Day 70 | 20.1 Days | Standard Deviation 11.63 |
| AmphoB+Fluc400 | Mean Days of Hospitalization | Day 14 | 15.1 Days | Standard Deviation 3.27 |
| AmphoB+Fluc400 | Mean Days of Hospitalization | Day 7 | 8.8 Days | Standard Deviation 2.39 |
| AmphoB+Fluc400 | Mean Days of Hospitalization | Day 42 | 17.4 Days | Standard Deviation 5.91 |
| AmphoB + Fluc800 | Mean Days of Hospitalization | Day 42 | 16.5 Days | Standard Deviation 7.03 |
| AmphoB + Fluc800 | Mean Days of Hospitalization | Day 70 | 16.6 Days | Standard Deviation 8.24 |
| AmphoB + Fluc800 | Mean Days of Hospitalization | Day 7 | 8.1 Days | Standard Deviation 2.53 |
| AmphoB + Fluc800 | Mean Days of Hospitalization | Day 14 | 13.6 Days | Standard Deviation 4.37 |
Secondary
Number of Cryptococcal Isolates With Antifungal Susceptibility
Isolates were collected at days 14 and 70 for assessment of antifungal susceptibility.
Time frame: Days 14 and 70
Population: The study team has since determined that the assay that was to be utilized did not have sufficient sensitivity/specificity for its intended purpose and therefore these results will not be generated.
Secondary
Number of Deaths
Number of deaths occurring on study. Day = Day relative to the first dose of study drug.
Time frame: 14, 42, and 70 days
Population: The Regulatory Safety Population was used in this analysis, which includes all subjects who were randomized, who received at least 1 dose of study drug, and who have any on-study data.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| AmphoB Standard | Number of Deaths | Day 43-70 | 1 Subjects |
| AmphoB Standard | Number of Deaths | Day 15-42 | 3 Subjects |
| AmphoB Standard | Number of Deaths | All Deaths | 10 Subjects |
| AmphoB Standard | Number of Deaths | Day 1-14 | 3 Subjects |
| AmphoB Standard | Number of Deaths | Day >70 | 3 Subjects |
| AmphoB+Fluc400 | Number of Deaths | Day 15-42 | 2 Subjects |
| AmphoB+Fluc400 | Number of Deaths | All Deaths | 8 Subjects |
| AmphoB+Fluc400 | Number of Deaths | Day 1-14 | 2 Subjects |
| AmphoB+Fluc400 | Number of Deaths | Day 43-70 | 2 Subjects |
| AmphoB+Fluc400 | Number of Deaths | Day >70 | 2 Subjects |
| AmphoB + Fluc800 | Number of Deaths | Day >70 | 2 Subjects |
| AmphoB + Fluc800 | Number of Deaths | Day 43-70 | 5 Subjects |
| AmphoB + Fluc800 | Number of Deaths | All Deaths | 9 Subjects |
| AmphoB + Fluc800 | Number of Deaths | Day 15-42 | 1 Subjects |
| AmphoB + Fluc800 | Number of Deaths | Day 1-14 | 1 Subjects |
Secondary
Number of Subjects Meeting the Key Efficacy Endpoint of Treatment Success
Treatment success is defined as a composite of the 3 mycologic and clinical measures: CSF culture conversion; neurologically stable or improved; and alive
Time frame: 14, 42, and 70 days
Population: The mITT population includes all subjects who are randomized to a treatment arm and receive any dose of study drug, who provide any outcome data, and who are determined to have met 2 key criteria for inclusion in the primary analysis - diagnosis of culture-proven cryptococcal meningitis and proven HIV infection.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| AmphoB Standard | Number of Subjects Meeting the Key Efficacy Endpoint of Treatment Success | Day 42 - Success | 33 Subjects |
| AmphoB Standard | Number of Subjects Meeting the Key Efficacy Endpoint of Treatment Success | Day 14 - Success | 19 Subjects |
| AmphoB Standard | Number of Subjects Meeting the Key Efficacy Endpoint of Treatment Success | Day 70 - Success | 33 Subjects |
| AmphoB+Fluc400 | Number of Subjects Meeting the Key Efficacy Endpoint of Treatment Success | Day 42 - Success | 35 Subjects |
| AmphoB+Fluc400 | Number of Subjects Meeting the Key Efficacy Endpoint of Treatment Success | Day 14 - Success | 13 Subjects |
| AmphoB+Fluc400 | Number of Subjects Meeting the Key Efficacy Endpoint of Treatment Success | Day 70 - Success | 36 Subjects |
| AmphoB + Fluc800 | Number of Subjects Meeting the Key Efficacy Endpoint of Treatment Success | Day 14 - Success | 22 Subjects |
| AmphoB + Fluc800 | Number of Subjects Meeting the Key Efficacy Endpoint of Treatment Success | Day 70 - Success | 32 Subjects |
| AmphoB + Fluc800 | Number of Subjects Meeting the Key Efficacy Endpoint of Treatment Success | Day 42 - Success | 33 Subjects |
Secondary
Number of Subjects Reporting Immune Reconstitution Inflammatory Syndrome (IRIS)
Number of subjects reporting immune reconstitution inflammatory syndrome (IRIS) following treatment. Day = Day relative to first dose of study drug
Time frame: 14, 42, and 70 days
Population: The Regulatory Safety population includes all subjects who were randomized, who receive at least 1 dose of study drug, and who have any on-study data
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| AmphoB Standard | Number of Subjects Reporting Immune Reconstitution Inflammatory Syndrome (IRIS) | Day 1 through 70 | 2 Subjects |
| AmphoB Standard | Number of Subjects Reporting Immune Reconstitution Inflammatory Syndrome (IRIS) | Day 1-14 | 0 Subjects |
| AmphoB Standard | Number of Subjects Reporting Immune Reconstitution Inflammatory Syndrome (IRIS) | Day 15-42 | 1 Subjects |
| AmphoB Standard | Number of Subjects Reporting Immune Reconstitution Inflammatory Syndrome (IRIS) | Day 43-70 | 1 Subjects |
| AmphoB+Fluc400 | Number of Subjects Reporting Immune Reconstitution Inflammatory Syndrome (IRIS) | Day 43-70 | 0 Subjects |
| AmphoB+Fluc400 | Number of Subjects Reporting Immune Reconstitution Inflammatory Syndrome (IRIS) | Day 1 through 70 | 0 Subjects |
| AmphoB+Fluc400 | Number of Subjects Reporting Immune Reconstitution Inflammatory Syndrome (IRIS) | Day 15-42 | 0 Subjects |
| AmphoB+Fluc400 | Number of Subjects Reporting Immune Reconstitution Inflammatory Syndrome (IRIS) | Day 1-14 | 0 Subjects |
| AmphoB + Fluc800 | Number of Subjects Reporting Immune Reconstitution Inflammatory Syndrome (IRIS) | Day 43-70 | 1 Subjects |
| AmphoB + Fluc800 | Number of Subjects Reporting Immune Reconstitution Inflammatory Syndrome (IRIS) | Day 1-14 | 0 Subjects |
| AmphoB + Fluc800 | Number of Subjects Reporting Immune Reconstitution Inflammatory Syndrome (IRIS) | Day 15-42 | 0 Subjects |
| AmphoB + Fluc800 | Number of Subjects Reporting Immune Reconstitution Inflammatory Syndrome (IRIS) | Day 1 through 70 | 1 Subjects |
Secondary
Number of Subjects With Cerebrospinal Fluid (CSF) Culture Conversion at Multiple Time Points
Number of subjects that have a negative fungal culture at Baseline, Day 14, Day 42, and Day 70.
Time frame: Baseline, 14, 42, and 70 days
Population: The modified Intent to Treat (mITT) population includes all subjects who are randomized to a treatment arm and receive any dose of study drug, who provide any outcome data, and who are determined to have met 2 key criteria for inclusion in the primary analysis - diagnosis of culture-proven cryptococcal meningitis and proven HIV infection.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| AmphoB Standard | Number of Subjects With Cerebrospinal Fluid (CSF) Culture Conversion at Multiple Time Points | Baseline - Negative | 0 Subjects |
| AmphoB Standard | Number of Subjects With Cerebrospinal Fluid (CSF) Culture Conversion at Multiple Time Points | Day 14 - Negative | 20 Subjects |
| AmphoB Standard | Number of Subjects With Cerebrospinal Fluid (CSF) Culture Conversion at Multiple Time Points | Day 42 - Negative | 35 Subjects |
| AmphoB Standard | Number of Subjects With Cerebrospinal Fluid (CSF) Culture Conversion at Multiple Time Points | Day 70 - Negative | 36 Subjects |
| AmphoB+Fluc400 | Number of Subjects With Cerebrospinal Fluid (CSF) Culture Conversion at Multiple Time Points | Day 70 - Negative | 39 Subjects |
| AmphoB+Fluc400 | Number of Subjects With Cerebrospinal Fluid (CSF) Culture Conversion at Multiple Time Points | Baseline - Negative | 0 Subjects |
| AmphoB+Fluc400 | Number of Subjects With Cerebrospinal Fluid (CSF) Culture Conversion at Multiple Time Points | Day 42 - Negative | 37 Subjects |
| AmphoB+Fluc400 | Number of Subjects With Cerebrospinal Fluid (CSF) Culture Conversion at Multiple Time Points | Day 14 - Negative | 13 Subjects |
| AmphoB + Fluc800 | Number of Subjects With Cerebrospinal Fluid (CSF) Culture Conversion at Multiple Time Points | Day 70 - Negative | 38 Subjects |
| AmphoB + Fluc800 | Number of Subjects With Cerebrospinal Fluid (CSF) Culture Conversion at Multiple Time Points | Day 14 - Negative | 22 Subjects |
| AmphoB + Fluc800 | Number of Subjects With Cerebrospinal Fluid (CSF) Culture Conversion at Multiple Time Points | Day 42 - Negative | 36 Subjects |
| AmphoB + Fluc800 | Number of Subjects With Cerebrospinal Fluid (CSF) Culture Conversion at Multiple Time Points | Baseline - Negative | 0 Subjects |