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

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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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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

Serious Adverse Events

Show Serious Adverse Events

Other Adverse Events

Show Other Adverse Events

More Information

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Certain Agreements:

Principal Investigators are NOT employed by the organization sponsoring the study.

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

The agreement is:

	The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.
	The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.
	Other disclosure agreement that restricts the right of the PI to discuss or publish trial results after the trial is completed.

Limitations and Caveats

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
No text entered.

Results Point of Contact:

Name/Title: Peter G. Pappas, MD
Organization: University of Alabama at Birmingham
phone: 205-934-9951
e-mail: pappas@uab.edu

Publications of Results:

Pappas PG, Chetchotisakd P, Larsen RA, Manosuthi W, Morris MI, Anekthananon T, Sungkanuparph S, Supparatpinyo K, Nolen TL, Zimmer LO, Kendrick AS, Johnson P, Sobel JD, Filler SG. A phase II randomized trial of amphotericin B alone or combined with fluconazole in the treatment of HIV-associated cryptococcal meningitis. Clin Infect Dis. 2009 Jun 15;48(12):1775-83.

Zimmer LO, Nolen TL, Pramanpol S, Wallace D, Walker ME, Pappas P, Chetchotisakd P. International collaboration between US and Thailand on a clinical trial of treatment for HIV-associated cryptococcal meningitis. Contemp Clin Trials. 2010 Jan;31(1):34-43. Epub 2009 Nov 6.

Responsible Party:	National Institute of Allergy and Infectious Diseases (NIAID)
ClinicalTrials.gov Identifier:	NCT00145249 History of Changes
Other Study ID Numbers:	03-154, BAMSG 3-01
Study First Received:	September 2, 2005
Results First Received:	March 18, 2010
Last Updated:	May 10, 2012
Health Authority:	Thailand: Ethical Committee United States: Federal Government United States: Food and Drug Administration United States: Institutional Review Board

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