Amphotericin Alone or in Combination With Fluconazole for AIDS-Associated Meningitis

• Sponsor: National Institute of Allergy and Infectious Diseases (NIAID) (NIH)
• Overall Status: Completed
• CT.gov ID: NCT00145249
• Collaborator: (none)
• Enrollment: 143
• Locations: 15
• Arms: 3
• Duration (Months): 35
• Patients Per Site: 9.5
• Patients Per Site Per Month: 0.3

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Cryptococcal Meningitis	Drug: Amphotericin B; Drug: Fluconazole	Phase 2

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 143 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase II Randomized Trial of Amphotericin B Alone or Combined With Fluconazole in the Treatment of AIDS-Associated Cryptococcal Meningitis
• Study Start Date: May 1, 2005
• Actual Primary Completion Date: Apr 1, 2008
• Actual Study Completion Date: Apr 1, 2008

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Standard Therapy 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.	Drug: Amphotericin 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.; Drug: Fluconazole; 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.
Experimental: Fluconazole Low Dose 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.	Drug: Amphotericin 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.; Drug: Fluconazole; 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.
Experimental: Fluconazole High Dose 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.	Drug: Amphotericin 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.; Drug: Fluconazole; 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.

Outcome Measures

Primary Outcome Measures

1. 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.

2. 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 Outcome Measures

1. Number of Deaths [14, 42, and 70 days]

   Number of deaths occurring on study. Day = Day relative to the first dose of study drug.

2. 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.

3. 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

4. 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

5. 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.

6. Number of Cryptococcal Isolates With Antifungal Susceptibility [Days 14 and 70]

   Isolates were collected at days 14 and 70 for assessment of antifungal susceptibility.

7. 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.

8. 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.

9. 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.

10. 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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 13 Years and Older
• Sexes Eligible for Study: All
• Accepts 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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Alabama at Birmingham	Birmingham	Alabama	United States	35255
2	University of Southern California	Los Angeles	California	United States	90033
3	Harbor-UCLA Medical Center	Los Angeles	California	United States	90502
4	University of Colorado	Denver	Colorado	United States	80291-0238
5	University of Florida	Gainesville	Florida	United States	32610
6	University of Miami	Miami	Florida	United States	33136-1096
7	Tulane University Health Sciences Center	New Orleans	Louisiana	United States	70112
8	Harper University Hospital	Detroit	Michigan	United States	48201
9	Texas Medical Center - Michael E. DeBakey Veterans Affairs	Houston	Texas	United States	77030
10	The University of Texas Health Science Center at Houston	Houston	Texas	United States	77030
11	Ramathibodi Hospital, Mahidol University	Bangkok		Thailand	10400
12	Mahidol University - Siriraj Hospital - Medicine	Bangkok		Thailand	10700
13	Chiang Mai University	Chiang Mai		Thailand	50200
14	Khon Kaen University	Khon Kaen		Thailand	40002
15	Bamrasnaradura Institution	Nonthaburi		Thailand	11000

Sponsors and Collaborators

• National Institute of Allergy and Infectious Diseases (NIAID)

Investigators

None specified.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: National Institute of Allergy and Infectious Diseases (NIAID)
• ClinicalTrials.gov Identifier: NCT00145249
• Other Study ID Numbers: 03-154; BAMSG 3-01
• First Posted: Sep 5, 2005
• Last Update Posted: May 16, 2012
• Last Verified: Oct 1, 2009

• Keywords provided by National Institute of Allergy and Infectious Diseases (NIAID): Bacterial infections, HIV infection, cryptococcal meningitis
• Additional relevant MeSH terms: Meningitis, Cryptococcal; Meningitis; Fluconazole; Amphotericin B; Liposomal amphotericin B

Study Results

Participant Flow

Recruitment Details	Subjects were screened and enrolled at 10 sites in the US and 5 sites in Thailand.

Arm/Group Title	AmphoB Standard	AmphoB+Fluc400	AmphoB + Fluc800
Arm/Group Description	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.	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.	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.
Period Title: Overall Study
STARTED	47	48	48
COMPLETED	36	33	31
NOT COMPLETED	11	15	17

Baseline Characteristics

Arm/Group Title	AmphoB Standard	AmphoB+Fluc400	AmphoB + Fluc800	Total
Arm/Group Description	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.	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.	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 of all reporting groups
Overall Participants	45	47	49	141
Age (Count of Participants)
<=18 years	0 0%	0 0%	1 2%	1 0.7%
Between 18 and 65 years	45 100%	47 100%	47 95.9%	139 98.6%
>=65 years	0 0%	0 0%	1 2%	1 0.7%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	37.1 (8.47)	36.5 (8.21)	35.9 (9.44)	36.5 (8.69)
Sex: Female, Male (Count of Participants)
Female	16 35.6%	15 31.9%	18 36.7%	49 34.8%
Male	29 64.4%	32 68.1%	31 63.3%	92 65.2%
Region of Enrollment (participants) [Number]
United States	14 31.1%	14 29.8%	14 28.6%	42 29.8%
Thailand	31 68.9%	33 70.2%	35 71.4%	99 70.2%

Outcome Measures

1. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

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/Group Title	AmphoB Standard	AmphoB+Fluc400	AmphoB + Fluc800
Arm/Group Description	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.	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.	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.
Measure Participants	45	47	49
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

2. Primary Outcome

Title	Number of Dose-limiting Toxicities Attributed to Treatment Regimens
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

Outcome Measure Data

Analysis Population Description

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/Group Title	AmphoB Standard	AmphoB+Fluc400	AmphoB + Fluc800
Arm/Group Description	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.	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.	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.
Measure Participants	45	47	49
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

3. Secondary Outcome

Title	Number of Deaths
Description	Number of deaths occurring on study. Day = Day relative to the first dose of study drug.
Time Frame	14, 42, and 70 days

Outcome Measure Data

Analysis Population Description

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/Group Title	AmphoB Standard	AmphoB+Fluc400	AmphoB + Fluc800
Arm/Group Description	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.	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.	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.
Measure Participants	45	47	49
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

4. Secondary Outcome

Title	Number of Subjects With Cerebrospinal Fluid (CSF) Culture Conversion at Multiple Time Points
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

Outcome Measure Data

Analysis Population Description

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/Group Title	AmphoB Standard	AmphoB+Fluc400	AmphoB + Fluc800
Arm/Group Description	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.	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.	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.
Measure Participants	46	48	41
Baseline - Negative	0	0	0
Day 14 - Negative	20	13	22
Day 42 - Negative	35	37	36
Day 70 - Negative	36	39	38

5. Secondary Outcome

Title	Number of Subjects Meeting the Key Efficacy Endpoint of Treatment Success
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

Outcome Measure Data

Analysis Population Description

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/Group Title	AmphoB Standard	AmphoB+Fluc400	AmphoB + Fluc800
Arm/Group Description	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.	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.	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.
Measure Participants	46	48	41
Day 14 - Success	19	13	22
Day 42 - Success	33	35	33
Day 70 - Success	33	36	32

6. Secondary Outcome

Title	Number of Subjects Reporting Immune Reconstitution Inflammatory Syndrome (IRIS)
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

Outcome Measure Data

Analysis Population Description

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/Group Title	AmphoB Standard	AmphoB+Fluc400	AmphoB + Fluc800
Arm/Group Description	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.	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.	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.
Measure Participants	45	47	49
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

7. Secondary Outcome

Title	Mean Days of Hospitalization
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

Outcome Measure Data

Analysis Population Description

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/Group Title	AmphoB Standard	AmphoB+Fluc400	AmphoB + Fluc800
Arm/Group Description	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.	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.	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.
Measure Participants	46	48	41
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)

8. Secondary Outcome

Title	Number of Cryptococcal Isolates With Antifungal Susceptibility
Description	Isolates were collected at days 14 and 70 for assessment of antifungal susceptibility.
Time Frame	Days 14 and 70

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	AmphoB Standard	AmphoB+Fluc400	AmphoB + Fluc800
Arm/Group Description	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.	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.	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.
Measure Participants	0	0	0

9. Secondary Outcome

Title	Mean Change in Neurological Exam Score From Baseline - Day 14
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

Outcome Measure Data

Analysis Population Description

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/Group Title	AmphoB Standard	AmphoB+Fluc400	AmphoB + Fluc800
Arm/Group Description	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.	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.	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.
Measure Participants	40	43	40
Mean (Standard Deviation) [Scores on a scale]	0.5 (4.07)	2.1 (3.74)	3.5 (6.25)

10. Secondary Outcome

Title	Mean Change in Neurological Exam Score From Baseline - Day 42
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

Outcome Measure Data

Analysis Population Description

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/Group Title	AmphoB Standard	AmphoB+Fluc400	AmphoB + Fluc800
Arm/Group Description	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.	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.	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.
Measure Participants	37	39	37
Mean (Standard Deviation) [Scores on a scale]	1.6 (2.58)	1.8 (4.42)	3.3 (7.9)

11. Secondary Outcome

Title	Mean Change in Neurological Exam Score From Baseline - Day 70
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

Outcome Measure Data

Analysis Population Description

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/Group Title	AmphoB Standard	AmphoB+Fluc400	AmphoB + Fluc800
Arm/Group Description	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.	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.	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.
Measure Participants	37	34	30
Mean (Standard Deviation) [Scores on a scale]	1.5 (3.28)	2.2 (3.58)	4.2 (6.84)

12. Secondary Outcome

Title	Mean Change in Neurological Exam Score From Baseline - Day 168
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

Outcome Measure Data

Analysis Population Description

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/Group Title	AmphoB Standard	AmphoB+Fluc400	AmphoB + Fluc800
Arm/Group Description	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.	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.	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.
Measure Participants	33	27	28
Mean (Standard Deviation) [Scores on a scale]	2.0 (2.28)	2.8 (3.92)	4.4 (7.58)

Adverse Events

Time Frame	Reported Adverse Events (AEs) include events starting on or after Day 0 and on or before Day 100.
Adverse Event Reporting Description	If a subject experienced more than 1 of a given AE, the subjects is counted only once for that AE. If a subject experienced more than one AE in a system organ class (SOC), the subject is counted only once in that SOC.
Arm/Group Title	AmphoB Standard		AmphoB+Fluc400		AmphoB + Fluc800
Arm/Group Description	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.		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.		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.
All Cause Mortality
	AmphoB Standard		AmphoB+Fluc400		AmphoB + Fluc800
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	AmphoB Standard		AmphoB+Fluc400		AmphoB + Fluc800
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	22/45 (48.9%)		17/47 (36.2%)		26/49 (53.1%)
Blood and lymphatic system disorders
Neutropenia	1/45 (2.2%)		0/47 (0%)		2/49 (4.1%)
Anaemia	2/45 (4.4%)		0/47 (0%)		0/49 (0%)
Thrombocytopenia	0/45 (0%)		0/47 (0%)		1/49 (2%)
Cardiac disorders
Cardiac failure congestive	0/45 (0%)		0/47 (0%)		1/49 (2%)
Cardio-respiratory arrest	0/45 (0%)		0/47 (0%)		1/49 (2%)
Congestive cardiomyopathy	0/45 (0%)		0/47 (0%)		1/49 (2%)
Eye disorders
Papilloedema	0/45 (0%)		0/47 (0%)		1/49 (2%)
Gastrointestinal disorders
Abdominal pain	0/45 (0%)		1/47 (2.1%)		0/49 (0%)
Vomiting	0/45 (0%)		0/47 (0%)		1/49 (2%)
General disorders
Pyrexia	0/45 (0%)		1/47 (2.1%)		1/49 (2%)
Hepatobiliary disorders
Cholangitis	0/45 (0%)		0/47 (0%)		1/49 (2%)
Hepatitis	0/45 (0%)		0/47 (0%)		1/49 (2%)
Hepatitis acute	1/45 (2.2%)		0/47 (0%)		0/49 (0%)
Immune system disorders
Immune reconstitution syndrome	2/45 (4.4%)		0/47 (0%)		1/49 (2%)
Hypersensitivity	1/45 (2.2%)		0/47 (0%)		0/49 (0%)
Infections and infestations
Sepsis	4/45 (8.9%)		3/47 (6.4%)		0/49 (0%)
Meningitis cryptococcal	2/45 (4.4%)		1/47 (2.1%)		1/49 (2%)
Pneumocystis jiroveci pneumonia	1/45 (2.2%)		2/47 (4.3%)		1/49 (2%)
Sinusitis	0/45 (0%)		0/47 (0%)		2/49 (4.1%)
AIDS related complication	0/45 (0%)		0/47 (0%)		1/49 (2%)
Arthritis bacterial	1/45 (2.2%)		0/47 (0%)		0/49 (0%)
End stage AIDS	0/45 (0%)		1/47 (2.1%)		0/49 (0%)
Escherichia sepsis	0/45 (0%)		0/47 (0%)		1/49 (2%)
Herpes zoster	1/45 (2.2%)		0/47 (0%)		0/49 (0%)
Pneumonia	0/45 (0%)		0/47 (0%)		1/49 (2%)
Pseudomonal bacteraemia	0/45 (0%)		0/47 (0%)		1/49 (2%)
Sepsis syndrome	1/45 (2.2%)		0/47 (0%)		0/49 (0%)
Staphylococcal infection	1/45 (2.2%)		0/47 (0%)		0/49 (0%)
Toxoplasmosis	0/45 (0%)		0/47 (0%)		1/49 (2%)
Injury, poisoning and procedural complications
Splenic rupture	0/45 (0%)		1/47 (2.1%)		0/49 (0%)
Subdural haematoma	0/45 (0%)		0/47 (0%)		1/49 (2%)
Investigations
CSF pressure increased	0/45 (0%)		0/47 (0%)		1/49 (2%)
Prothrombin time prolonged	0/45 (0%)		0/47 (0%)		1/49 (2%)
Metabolism and nutrition disorders
Dehydration	0/45 (0%)		0/47 (0%)		3/49 (6.1%)
Cachexia	0/45 (0%)		0/47 (0%)		1/49 (2%)
Hyponatraemia	0/45 (0%)		1/47 (2.1%)		0/49 (0%)
Musculoskeletal and connective tissue disorders
Back pain	1/45 (2.2%)		0/47 (0%)		0/49 (0%)
Pain in extremity	0/45 (0%)		0/47 (0%)		1/49 (2%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Central nervous system lymphoma	0/45 (0%)		0/47 (0%)		1/49 (2%)
Kaposi's sarcoma	1/45 (2.2%)		0/47 (0%)		0/49 (0%)
Nervous system disorders
Intracranial pressure increased	3/45 (6.7%)		2/47 (4.3%)		2/49 (4.1%)
Convulsion	2/45 (4.4%)		3/47 (6.4%)		0/49 (0%)
Headache	1/45 (2.2%)		1/47 (2.1%)		1/49 (2%)
Brain compression	1/45 (2.2%)		0/47 (0%)		0/49 (0%)
Cerebral haemorrhage	0/45 (0%)		0/47 (0%)		1/49 (2%)
Cerebral infarction	0/45 (0%)		0/47 (0%)		1/49 (2%)
Depressed level of consciousness	0/45 (0%)		1/47 (2.1%)		0/49 (0%)
Hemiparesis	1/45 (2.2%)		0/47 (0%)		0/49 (0%)
Hemiplegia	0/45 (0%)		1/47 (2.1%)		0/49 (0%)
Psychiatric disorders
Psychotic disorder	0/45 (0%)		0/47 (0%)		1/49 (2%)
Reproductive system and breast disorders
Vaginal haemorrhage	1/45 (2.2%)		0/47 (0%)		0/49 (0%)
Respiratory, thoracic and mediastinal disorders
Respiratory failure	1/45 (2.2%)		1/47 (2.1%)		2/49 (4.1%)
Pleurisy	0/45 (0%)		1/47 (2.1%)		0/49 (0%)
Other (Not Including Serious) Adverse Events
	AmphoB Standard		AmphoB+Fluc400		AmphoB + Fluc800
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	44/45 (97.8%)		47/47 (100%)		49/49 (100%)
Blood and lymphatic system disorders
Anaemia	21/45 (46.7%)		27/47 (57.4%)		24/49 (49%)
Thrombocytopenia	2/45 (4.4%)		4/47 (8.5%)		4/49 (8.2%)
Neutropenia	2/45 (4.4%)		1/47 (2.1%)		3/49 (6.1%)
Eye disorders
Papilloedema	2/45 (4.4%)		1/47 (2.1%)		3/49 (6.1%)
Gastrointestinal disorders
Vomiting	14/45 (31.1%)		14/47 (29.8%)		16/49 (32.7%)
Nausea	4/45 (8.9%)		14/47 (29.8%)		16/49 (32.7%)
Constipation	6/45 (13.3%)		4/47 (8.5%)		9/49 (18.4%)
Diarrhoea	3/45 (6.7%)		6/47 (12.8%)		6/49 (12.2%)
Dyspepsia	2/45 (4.4%)		4/47 (8.5%)		0/49 (0%)
Abdominal Pain	1/45 (2.2%)		3/47 (6.4%)		0/49 (0%)
General disorders
Pyrexia	2/45 (4.4%)		4/47 (8.5%)		6/49 (12.2%)
Chills	4/45 (8.9%)		4/47 (8.5%)		2/49 (4.1%)
Asthenia	1/45 (2.2%)		2/47 (4.3%)		3/49 (6.1%)
Pain	0/45 (0%)		3/47 (6.4%)		0/49 (0%)
Hepatobiliary disorders
Hyperbilirubinaemia	0/45 (0%)		3/47 (6.4%)		0/49 (0%)
Immune system disorders
Immune reconstitution syndrome	3/45 (6.7%)		0/47 (0%)		1/49 (2%)
Infections and infestations
Sepsis	5/45 (11.1%)		7/47 (14.9%)		6/49 (12.2%)
Herpes simplex	4/45 (8.9%)		4/47 (8.5%)		5/49 (10.2%)
Sinusitis	7/45 (15.6%)		0/47 (0%)		6/49 (12.2%)
Bacteraemia	1/45 (2.2%)		3/47 (6.4%)		5/49 (10.2%)
Herpes zoster	3/45 (6.7%)		4/47 (8.5%)		1/49 (2%)
Oral candidiasis	2/45 (4.4%)		2/47 (4.3%)		4/49 (8.2%)
Pneumocystis jiroveci pneumonia	3/45 (6.7%)		3/47 (6.4%)		1/49 (2%)
Upper respiratory tract infection	0/45 (0%)		0/47 (0%)		4/49 (8.2%)
Investigations
Blood creatinine increased	4/45 (8.9%)		4/47 (8.5%)		2/49 (4.1%)
Metabolism and nutrition disorders
Hypokalaemia	38/45 (84.4%)		38/47 (80.9%)		39/49 (79.6%)
Hypomagnesaemia	27/45 (60%)		33/47 (70.2%)		31/49 (63.3%)
Anorexia	12/45 (26.7%)		8/47 (17%)		7/49 (14.3%)
Hyponatraemia	2/45 (4.4%)		7/47 (14.9%)		6/49 (12.2%)
Hyperkalaemia	5/45 (11.1%)		2/47 (4.3%)		3/49 (6.1%)
Dehydration	1/45 (2.2%)		1/47 (2.1%)		3/49 (6.1%)
Musculoskeletal and connective tissue disorders
Back pain	3/45 (6.7%)		4/47 (8.5%)		1/49 (2%)
Nervous system disorders
Headache	10/45 (22.2%)		13/47 (27.7%)		14/49 (28.6%)
Convulsion	5/45 (11.1%)		5/47 (10.6%)		2/49 (4.1%)
Intracranial pressure increased	3/45 (6.7%)		2/47 (4.3%)		2/49 (4.1%)
Psychiatric disorders
Insomnia	11/45 (24.4%)		7/47 (14.9%)		11/49 (22.4%)
Depression	0/45 (0%)		0/47 (0%)		3/49 (6.1%)
Renal and urinary disorders
Renal failure	0/45 (0%)		6/47 (12.8%)		0/49 (0%)
Respiratory, thoracic and mediastinal disorders
Cough	1/45 (2.2%)		3/47 (6.4%)		2/49 (4.1%)
Skin and subcutaneous tissue disorders
Rash papular	4/45 (8.9%)		4/47 (8.5%)		3/49 (6.1%)
Rash	2/45 (4.4%)		2/47 (4.3%)		5/49 (10.2%)
Pruritus	1/45 (2.2%)		2/47 (4.3%)		3/49 (6.1%)
Seborrhoeic dermatitis	0/45 (0%)		3/47 (6.4%)		0/49 (0%)
Vascular disorders
Phlebitis	4/45 (8.9%)		5/47 (10.6%)		8/49 (16.3%)
Thrombophlebitis	2/45 (4.4%)		4/47 (8.5%)		6/49 (12.2%)
Hypotension	4/45 (8.9%)		2/47 (4.3%)		2/49 (4.1%)
Hypertension	1/45 (2.2%)		3/47 (6.4%)		2/49 (4.1%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

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.