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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
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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 ]
  Show Outcome Measure 1

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

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

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

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

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

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

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

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

10.  Secondary:   Mean Change in Neurological Exam Score From Baseline - Day 42   [ Time Frame: Baseline and Day 42 ]
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11.  Secondary:   Mean Change in Neurological Exam Score From Baseline - Day 70   [ Time Frame: Baseline and Day 70 ]
  Show Outcome Measure 11

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


  Serious Adverse Events
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  Other Adverse Events
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Time Frame Reported Adverse Events (AEs) include events starting on or after Day 0 and on or before Day 100.
Additional 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.

Frequency Threshold
Threshold above which other adverse events are reported   5%  

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.

Other Adverse Events
    AmphoB Standard     AmphoB+Fluc400     AmphoB + Fluc800  
Total, other (not including serious) adverse events        
# participants affected / at risk     44/45     47/47     49/49  
Blood and lymphatic system disorders        
Anaemia * 1      
# participants affected / at risk     21/45 (46.67%)     27/47 (57.45%)     24/49 (48.98%)  
Thrombocytopenia * 1      
# participants affected / at risk     2/45 (4.44%)     4/47 (8.51%)     4/49 (8.16%)  
Neutropenia * 1      
# participants affected / at risk     2/45 (4.44%)     1/47 (2.13%)     3/49 (6.12%)  
Eye disorders        
Papilloedema * 1      
# participants affected / at risk     2/45 (4.44%)     1/47 (2.13%)     3/49 (6.12%)  
Gastrointestinal disorders        
Vomiting * 1      
# participants affected / at risk     14/45 (31.11%)     14/47 (29.79%)     16/49 (32.65%)  
Nausea * 1      
# participants affected / at risk     4/45 (8.89%)     14/47 (29.79%)     16/49 (32.65%)  
Constipation * 1      
# participants affected / at risk     6/45 (13.33%)     4/47 (8.51%)     9/49 (18.37%)  
Diarrhoea * 1      
# participants affected / at risk     3/45 (6.67%)     6/47 (12.77%)     6/49 (12.24%)  
Dyspepsia * 1      
# participants affected / at risk     2/45 (4.44%)     4/47 (8.51%)     0/49 (0.00%)  
Abdominal Pain * 1      
# participants affected / at risk     1/45 (2.22%)     3/47 (6.38%)     0/49 (0.00%)  
General disorders        
Pyrexia * 1      
# participants affected / at risk     2/45 (4.44%)     4/47 (8.51%)     6/49 (12.24%)  
Chills * 1      
# participants affected / at risk     4/45 (8.89%)     4/47 (8.51%)     2/49 (4.08%)  
Asthenia * 1      
# participants affected / at risk     1/45 (2.22%)     2/47 (4.26%)     3/49 (6.12%)  
Pain * 1      
# participants affected / at risk     0/45 (0.00%)     3/47 (6.38%)     0/49 (0.00%)  
Hepatobiliary disorders        
Hyperbilirubinaemia * 1      
# participants affected / at risk     0/45 (0.00%)     3/47 (6.38%)     0/49 (0.00%)  
Immune system disorders        
Immune reconstitution syndrome * 1      
# participants affected / at risk     3/45 (6.67%)     0/47 (0.00%)     1/49 (2.04%)  
Infections and infestations        
Sepsis * 1      
# participants affected / at risk     5/45 (11.11%)     7/47 (14.89%)     6/49 (12.24%)  
Herpes simplex * 1      
# participants affected / at risk     4/45 (8.89%)     4/47 (8.51%)     5/49 (10.20%)  
Sinusitis * 1      
# participants affected / at risk     7/45 (15.56%)     0/47 (0.00%)     6/49 (12.24%)  
Bacteraemia * 1      
# participants affected / at risk     1/45 (2.22%)     3/47 (6.38%)     5/49 (10.20%)  
Herpes zoster * 1      
# participants affected / at risk     3/45 (6.67%)     4/47 (8.51%)     1/49 (2.04%)  
Oral candidiasis * 1      
# participants affected / at risk     2/45 (4.44%)     2/47 (4.26%)     4/49 (8.16%)  
Pneumocystis jiroveci pneumonia * 1      
# participants affected / at risk     3/45 (6.67%)     3/47 (6.38%)     1/49 (2.04%)  
Upper respiratory tract infection * 1      
# participants affected / at risk     0/45 (0.00%)     0/47 (0.00%)     4/49 (8.16%)  
Investigations        
Blood creatinine increased * 1      
# participants affected / at risk     4/45 (8.89%)     4/47 (8.51%)     2/49 (4.08%)  
Metabolism and nutrition disorders        
Hypokalaemia * 1      
# participants affected / at risk     38/45 (84.44%)     38/47 (80.85%)     39/49 (79.59%)  
Hypomagnesaemia * 1      
# participants affected / at risk     27/45 (60.00%)     33/47 (70.21%)     31/49 (63.27%)  
Anorexia * 1      
# participants affected / at risk     12/45 (26.67%)     8/47 (17.02%)     7/49 (14.29%)  
Hyponatraemia * 1      
# participants affected / at risk     2/45 (4.44%)     7/47 (14.89%)     6/49 (12.24%)  
Hyperkalaemia * 1      
# participants affected / at risk     5/45 (11.11%)     2/47 (4.26%)     3/49 (6.12%)  
Dehydration * 1      
# participants affected / at risk     1/45 (2.22%)     1/47 (2.13%)     3/49 (6.12%)  
Musculoskeletal and connective tissue disorders        
Back pain * 1      
# participants affected / at risk     3/45 (6.67%)     4/47 (8.51%)     1/49 (2.04%)  
Nervous system disorders        
Headache * 1      
# participants affected / at risk     10/45 (22.22%)     13/47 (27.66%)     14/49 (28.57%)  
Convulsion * 1      
# participants affected / at risk     5/45 (11.11%)     5/47 (10.64%)     2/49 (4.08%)  
Intracranial pressure increased * 1      
# participants affected / at risk     3/45 (6.67%)     2/47 (4.26%)     2/49 (4.08%)  
Psychiatric disorders        
Insomnia * 1      
# participants affected / at risk     11/45 (24.44%)     7/47 (14.89%)     11/49 (22.45%)  
Depression * 1      
# participants affected / at risk     0/45 (0.00%)     0/47 (0.00%)     3/49 (6.12%)  
Renal and urinary disorders        
Renal failure * 1      
# participants affected / at risk     0/45 (0.00%)     6/47 (12.77%)     0/49 (0.00%)  
Respiratory, thoracic and mediastinal disorders        
Cough * 1      
# participants affected / at risk     1/45 (2.22%)     3/47 (6.38%)     2/49 (4.08%)  
Skin and subcutaneous tissue disorders        
Rash papular * 1      
# participants affected / at risk     4/45 (8.89%)     4/47 (8.51%)     3/49 (6.12%)  
Rash * 1      
# participants affected / at risk     2/45 (4.44%)     2/47 (4.26%)     5/49 (10.20%)  
Pruritus * 1      
# participants affected / at risk     1/45 (2.22%)     2/47 (4.26%)     3/49 (6.12%)  
Seborrhoeic dermatitis * 1      
# participants affected / at risk     0/45 (0.00%)     3/47 (6.38%)     0/49 (0.00%)  
Vascular disorders        
Phlebitis * 1      
# participants affected / at risk     4/45 (8.89%)     5/47 (10.64%)     8/49 (16.33%)  
Thrombophlebitis * 1      
# participants affected / at risk     2/45 (4.44%)     4/47 (8.51%)     6/49 (12.24%)  
Hypotension * 1      
# participants affected / at risk     4/45 (8.89%)     2/47 (4.26%)     2/49 (4.08%)  
Hypertension * 1      
# participants affected / at risk     1/45 (2.22%)     3/47 (6.38%)     2/49 (4.08%)  
* Events were collected by non-systematic assessment
1 Term from vocabulary, MedDRA (8.0)



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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:
unchecked 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.
unchecked 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:


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