Comment Period Extended to 3/23/2015 for Notice of Proposed Rulemaking (NPRM) for FDAAA 801 and NIH Draft Reporting Policy for NIH-Funded Trials
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Amphotericin Alone or in Combination With Fluconazole for AIDS-Associated Meningitis

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
National Institute of Allergy and Infectious Diseases (NIAID)
ClinicalTrials.gov Identifier:
NCT00145249
First received: September 2, 2005
Last updated: May 10, 2012
Last verified: October 2009
History of Changes
Results First Received: March 18, 2010  
Study Type: Interventional
Study Design: Allocation: Randomized;   Endpoint Classification: Safety/Efficacy Study;   Intervention Model: Parallel Assignment;   Masking: Open Label;   Primary Purpose: Treatment
Condition: Cryptococcal Meningitis
Interventions: Drug: Amphotericin B
Drug: Fluconazole

  Participant Flow
  Hide Participant Flow

Recruitment Details
Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
Subjects were screened and enrolled at 10 sites in the US and 5 sites in Thailand.

Pre-Assignment Details
Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
No text entered.

Reporting Groups
  Description
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.
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.
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.

Participant Flow:   Overall Study
    AmphoB Standard     AmphoB+Fluc400     AmphoB + Fluc800  
STARTED     47 [1]   48 [2]   48 [3]
COMPLETED     36     33     31  
NOT COMPLETED     11     15     17  
[1] 47 subjects randomized; 45 subjects treated
[2] 48 subjects randomized; 47 subjects treated-2 subjects randomized to AmphoB rec'd AmphoB+Fluc400
[3] 48 subjects randomized; 49 treated-3 subjects randomized to AmphoB+Fluc400 rec'd AmphoB+Fluc800



  Baseline Characteristics
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Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
No text entered.

Reporting Groups
  Description
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.
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.
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.
Total Total of all reporting groups

Baseline Measures
    AmphoB Standard     AmphoB+Fluc400     AmphoB + Fluc800     Total  
Number of Participants  
[units: participants]
 		  45     47     49     141  
Age  
[units: participants]
 		       
<=18 years     0     0     1     1  
Between 18 and 65 years     45     47     47     139  
>=65 years     0     0     1     1  
Age  
[units: years]
Mean ± Standard Deviation 		  37.1  ± 8.47     36.5  ± 8.21     35.9  ± 9.44     36.5  ± 8.69  
Gender  
[units: participants]
 		       
Female     16     15     18     49  
Male     29     32     31     92  
Region of Enrollment  
[units: participants]
 		       
United States     14     14     14     42  
Thailand     31     33     35     99  



  Outcome Measures
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1.  Primary:   Number of Grade 3-5 Adverse Experiences That Are Definitely or Probably Related to Study Drug   [ Time Frame: Day 100 ]

Measure Type Primary
Measure Title Number of Grade 3-5 Adverse Experiences That Are Definitely or Probably Related to Study Drug
Measure Description

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  
Safety Issue Yes  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
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.

Reporting Groups
  Description
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.
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.
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.

Measured Values
    AmphoB Standard     AmphoB+Fluc400     AmphoB + Fluc800  
Number of Participants Analyzed  
[units: participants]
 		  45     47     49  
Number of Grade 3-5 Adverse Experiences That Are Definitely or Probably Related to Study Drug  
[units: Events]
 		     
Hypomagnesaemia     2     1     0  
Hypokalaemia     0     0     1  
Anaemia     1     1     0  
Drug intolerance     1     0     0  
Creatinine renal clearance increased     0     0     1  
Psychotic disorder     0     0     1  

No statistical analysis provided for Number of Grade 3-5 Adverse Experiences That Are Definitely or Probably Related to Study Drug



2.  Primary:   Number of Dose-limiting Toxicities Attributed to Treatment Regimens   [ Time Frame: Day 100 ]

Measure Type Primary
Measure Title Number of Dose-limiting Toxicities Attributed to Treatment Regimens
Measure Description

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  
Safety Issue Yes  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
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.

Reporting Groups
  Description
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.
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.
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.

Measured Values
    AmphoB Standard     AmphoB+Fluc400     AmphoB + Fluc800  
Number of Participants Analyzed  
[units: participants]
 		  45     47     49  
Number of Dose-limiting Toxicities Attributed to Treatment Regimens  
[units: Events]
 		     
All Events     6     7     14  
Blood creatinine increased     4     1     1  
Creatinine renal clearance decreased     0     1     2  
Creatinine renal clearance increased     0     0     2  
Renal failure     0     2     0  
Renal failure acute     0     1     1  
Azotaemia     0     0     1  
Renal impairment     0     0     1  
Nausea     0     0     1  
Vomiting     0     0     1  
Drug intolerance     1     1     0  
Chills     0     1     0  
Neutropenia     0     0     1  
Hepatitis acute     1     0     0  
Pneumonia     0     0     1  
Dehydration     0     0     1  
Respiratory failure     0     0     1  

No statistical analysis provided for Number of Dose-limiting Toxicities Attributed to Treatment Regimens



3.  Secondary:   Number of Deaths   [ Time Frame: 14, 42, and 70 days ]

Measure Type Secondary
Measure Title Number of Deaths
Measure Description

Number of deaths occurring on study.

Day = Day relative to the first dose of study drug.
Time Frame 14, 42, and 70 days  
Safety Issue Yes  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
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.

Reporting Groups
  Description
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.
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.
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.

Measured Values
    AmphoB Standard     AmphoB+Fluc400     AmphoB + Fluc800  
Number of Participants Analyzed  
[units: participants]
 		  45     47     49  
Number of Deaths  
[units: Subjects]
 		     
All Deaths     10     8     9  
Day 1-14     3     2     1  
Day 15-42     3     2     1  
Day 43-70     1     2     5  
Day >70     3     2     2  

No statistical analysis provided for Number of Deaths



4.  Secondary:   Number of Subjects With Cerebrospinal Fluid (CSF) Culture Conversion at Multiple Time Points   [ Time Frame: Baseline, 14, 42, and 70 days ]

Measure Type Secondary
Measure Title Number of Subjects With Cerebrospinal Fluid (CSF) Culture Conversion at Multiple Time Points
Measure Description 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  
Safety Issue No  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
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.

Reporting Groups
  Description
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.
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.
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.

Measured Values
    AmphoB Standard     AmphoB+Fluc400     AmphoB + Fluc800  
Number of Participants Analyzed  
[units: participants]
 		  46     48     41  
Number of Subjects With Cerebrospinal Fluid (CSF) Culture Conversion at Multiple Time Points  
[units: Subjects]
 		     
Baseline - Negative     0     0     0  
Day 14 - Negative     20     13     22  
Day 42 - Negative     35     37     36  
Day 70 - Negative     36     39     38  

No statistical analysis provided for Number of Subjects With Cerebrospinal Fluid (CSF) Culture Conversion at Multiple Time Points



5.  Secondary:   Number of Subjects Meeting the Key Efficacy Endpoint of Treatment Success   [ Time Frame: 14, 42, and 70 days ]

Measure Type Secondary
Measure Title Number of Subjects Meeting the Key Efficacy Endpoint of Treatment Success
Measure Description 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  
Safety Issue No  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
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.

Reporting Groups
  Description
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.
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.
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.

Measured Values
    AmphoB Standard     AmphoB+Fluc400     AmphoB + Fluc800  
Number of Participants Analyzed  
[units: participants]
 		  46     48     41  
Number of Subjects Meeting the Key Efficacy Endpoint of Treatment Success  
[units: Subjects]
 		     
Day 14 - Success     19     13     22  
Day 42 - Success     33     35     33  
Day 70 - Success     33     36     32  

No statistical analysis provided for Number of Subjects Meeting the Key Efficacy Endpoint of Treatment Success



6.  Secondary:   Number of Subjects Reporting Immune Reconstitution Inflammatory Syndrome (IRIS)   [ Time Frame: 14, 42, and 70 days ]

Measure Type Secondary
Measure Title Number of Subjects Reporting Immune Reconstitution Inflammatory Syndrome (IRIS)
Measure Description

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  
Safety Issue Yes  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
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

Reporting Groups
  Description
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.
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.
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.

Measured Values
    AmphoB Standard     AmphoB+Fluc400     AmphoB + Fluc800  
Number of Participants Analyzed  
[units: participants]
 		  45     47     49  
Number of Subjects Reporting Immune Reconstitution Inflammatory Syndrome (IRIS)  
[units: Subjects]
 		     
Day 1 through 70     2     0     1  
Day 1-14     0     0     0  
Day 15-42     1     0     0  
Day 43-70     1     0     1  

No statistical analysis provided for Number of Subjects Reporting Immune Reconstitution Inflammatory Syndrome (IRIS)



7.  Secondary:   Mean Days of Hospitalization   [ Time Frame: 7, 14, 42, and 70 days ]

Measure Type Secondary
Measure Title Mean Days of Hospitalization
Measure Description 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  
Safety Issue No  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
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.

Reporting Groups
  Description
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.
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.
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.

Measured Values
    AmphoB Standard     AmphoB+Fluc400     AmphoB + Fluc800  
Number of Participants Analyzed  
[units: participants]
 		  46     48     41  
Mean Days of Hospitalization  
[units: Days]
Mean ± Standard Deviation 		     
Day 7     8.9  ± 1.61     8.8  ± 2.39     8.1  ± 2.53  
Day 14     15.4  ± 1.78     15.1  ± 3.27     13.6  ± 4.37  
Day 42     16.3  ± 4.22     17.4  ± 5.91     16.5  ± 7.03  
Day 70     16.7  ± 4.54     20.1  ± 11.63     16.6  ± 8.24  

No statistical analysis provided for Mean Days of Hospitalization



8.  Secondary:   Number of Cryptococcal Isolates With Antifungal Susceptibility   [ Time Frame: Days 14 and 70 ]

Measure Type Secondary
Measure Title Number of Cryptococcal Isolates With Antifungal Susceptibility
Measure Description Isolates were collected at days 14 and 70 for assessment of antifungal susceptibility.
Time Frame Days 14 and 70  
Safety Issue No  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
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.

Reporting Groups
  Description
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.
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.
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.

Measured Values
    AmphoB Standard     AmphoB+Fluc400     AmphoB + Fluc800  
Number of Participants Analyzed  
[units: participants]
 		  0     0     0  
Number of Cryptococcal Isolates With Antifungal Susceptibility  
[units: Isolates]
 		           

No statistical analysis provided for Number of Cryptococcal Isolates With Antifungal Susceptibility



9.  Secondary:   Mean Change in Neurological Exam Score From Baseline - Day 14   [ Time Frame: Baseline and Day 14 ]

Measure Type Secondary
Measure Title Mean Change in Neurological Exam Score From Baseline - Day 14
Measure Description 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  
Safety Issue No  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
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.

Reporting Groups
  Description
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.
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.
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.

Measured Values
    AmphoB Standard     AmphoB+Fluc400     AmphoB + Fluc800  
Number of Participants Analyzed  
[units: participants]
 		  40     43     40  
Mean Change in Neurological Exam Score From Baseline - Day 14  
[units: Scores on a scale]
Mean ± Standard Deviation 		  0.5  ± 4.07     2.1  ± 3.74     3.5  ± 6.25  

No statistical analysis provided for Mean Change in Neurological Exam Score From Baseline - Day 14



10.  Secondary:   Mean Change in Neurological Exam Score From Baseline - Day 42   [ Time Frame: Baseline and Day 42 ]

Measure Type Secondary
Measure Title Mean Change in Neurological Exam Score From Baseline - Day 42
Measure Description 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  
Safety Issue No  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
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.

Reporting Groups
  Description
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.
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.
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.

Measured Values
    AmphoB Standard     AmphoB+Fluc400     AmphoB + Fluc800  
Number of Participants Analyzed  
[units: participants]
 		  37     39     37  
Mean Change in Neurological Exam Score From Baseline - Day 42  
[units: Scores on a scale]
Mean ± Standard Deviation 		  1.6  ± 2.58     1.8  ± 4.42     3.3  ± 7.9  

No statistical analysis provided for Mean Change in Neurological Exam Score From Baseline - Day 42



11.  Secondary:   Mean Change in Neurological Exam Score From Baseline - Day 70   [ Time Frame: Baseline and Day 70 ]

Measure Type Secondary
Measure Title Mean Change in Neurological Exam Score From Baseline - Day 70
Measure Description 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  
Safety Issue No  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
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.

Reporting Groups
  Description
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.
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.
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.

Measured Values
    AmphoB Standard     AmphoB+Fluc400     AmphoB + Fluc800  
Number of Participants Analyzed  
[units: participants]
 		  37     34     30  
Mean Change in Neurological Exam Score From Baseline - Day 70  
[units: Scores on a scale]
Mean ± Standard Deviation 		  1.5  ± 3.28     2.2  ± 3.58     4.2  ± 6.84  

No statistical analysis provided for Mean Change in Neurological Exam Score From Baseline - Day 70



12.  Secondary:   Mean Change in Neurological Exam Score From Baseline - Day 168   [ Time Frame: Baseline and Day 168 ]

Measure Type Secondary
Measure Title Mean Change in Neurological Exam Score From Baseline - Day 168
Measure Description 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  
Safety Issue No  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
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.

Reporting Groups
  Description
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.
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.
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.

Measured Values
    AmphoB Standard     AmphoB+Fluc400     AmphoB + Fluc800  
Number of Participants Analyzed  
[units: participants]
 		  33     27     28  
Mean Change in Neurological Exam Score From Baseline - Day 168  
[units: Scores on a scale]
Mean ± Standard Deviation 		  2.0  ± 2.28     2.8  ± 3.92     4.4  ± 7.58  

No statistical analysis provided for Mean Change in Neurological Exam Score From Baseline - Day 168




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  Limitations and Caveats
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Limitations of the study, such as early termination leading to small numbers of participants analyzed and technical problems with measurement leading to unreliable or uninterpretable data
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