Minocycline for HIV+ Cognitive Impairment in Uganda

This study has been terminated.
(The Neurologic AIDS Research Consortium Data Safety and Monitoring Board committee recommended to terminate the study early due to futility on 11/6/2009.)
Sponsor:
Collaborator:
Makerere University
Information provided by:
Johns Hopkins University
ClinicalTrials.gov Identifier:
NCT00855062
First received: March 2, 2009
Last updated: January 28, 2011
Last verified: January 2011
Results First Received: December 17, 2010  
Study Type: Interventional
Study Design: Allocation: Randomized;   Endpoint Classification: Safety/Efficacy Study;   Intervention Model: Single Group Assignment;   Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor);   Primary Purpose: Treatment
Conditions: HIV-associated Cognitive Impairment
HIV Infections
Interventions: Drug: minocycline
Drug: minocycline placebo capsule

  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
The recruitment period was from Mar 2008 to Oct 2009 when the study was stopped early (Data and Safety Monitoring Board (DSMB) decision based on futility) on Nov 2009. The study participants were recruited from the Infectious Disease Institute, Makerere University, Kampala, Uganda.

Pre-Assignment Details
Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
Total of 353 participants were screened; only 73 were randomized and thus 280 were not enrolled: 146 of them did not have cognitive impairment, 55 of them lacked laboratory inclusion criteria, and 79 of them had "others".

Reporting Groups
  Description
Minocycline Minocycline 100 mg orally every 12 hours
Placebo Placebo minocycline capsules every 12 hours

Participant Flow for 2 periods

Period 1:   Step1
    Minocycline     Placebo  
STARTED     36     37  
COMPLETED     26     26  
NOT COMPLETED     10     11  
Early Study Closure                 5                 7  
Adverse Event                 1                 1  
Protocol Violation                 1                 0  
Pregnancy                 1                 0  
Withdrawal by Subject                 2                 3  

Period 2:   Step2
    Minocycline     Placebo  
STARTED     19 [1]   21 [2]
COMPLETED     13     15  
NOT COMPLETED     6     6  
Early Study Closure                 6                 2  
Adverse Event                 0                 3  
Initiation of antiretroviral therapy/ART                 0                 1  
[1] 26 participants completed STEP1; however, only 19 out of the 26 decided to enroll in STEP2.
[2] 26 participants completed STEP1; however, only 21 out of the 26 decided to enroll in STEP2.



  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
Minocycline Minocycline 100 mg orally every 12 hours
Placebo Placebo minocycline capsules every 12 hours
Total Total of all reporting groups

Baseline Measures
    Minocycline     Placebo     Total  
Number of Participants  
[units: participants]
  36     37     73  
Age  
[units: participants]
     
<=18 years     0     0     0  
Between 18 and 65 years     36     37     73  
>=65 years     0     0     0  
Age  
[units: years]
Mean ± Standard Deviation
  37.3  ± 8.21     36.7  ± 7.17     37.0  ± 7.66  
Gender  
[units: participants]
     
Female     34     32     66  
Male     2     5     7  
Region of Enrollment  
[units: participants]
     
Uganda     36     37     73  
Baseline Memorial Sloan Kettering (MSK) Acquired Immune Deficiency Syndrome (AIDS) Dementia Scale [1]
[units: Participants]
     
Equivocal/subclinical     35     37     72  
Mild     1     0     1  
Baseline Cluster of Differentiation Four (CD4) Count  
[units: cells/mm^3]
Median ( Full Range )
  319  
  ( 251 to 469 )  
  305  
  ( 252 to 500 )  
  313  
  ( 251 to 500 )  
Baseline Log10(Human immunodeficiency virus (HIV) Ribonucleic Acid (RNA) Viral Load (VL))  
[units: copies/mL]
Log Mean ( Inter-Quartile Range )
  4.41  
  ( 4.09 to 4.94 )  
  4.59  
  ( 4.12 to 5.25 )  
  4.50  
  ( 4.10 to 5.10 )  
Baseline Karnofsky's Performance Score [2]
[units: Participants]
     
80 (Karnofsky Score)     1     2     3  
90 (Karnofsky Score)     35     34     69  
100 (Karnofsky Score)     0     1     1  
Baseline Instrumental Activities of Daily Living (IADL) [3]
[units: Participants]
     
Primarily cognitive problems     1     0     1  
Primarily physical problems     6     2     8  
Not having any difficulties on the tasks     29     35     64  
Baseline Overall Neurological Assessment  
[units: Participants]
     
Normal neurological assessment     26     30     56  
Central Nervous System (CNS) abnormality only     4     5     9  
Peripheral Nervous System (PNS) abnormality only     4     1     5  
CNS and PNS abnormality     1     1     2  
Can not assess     1     0     1  
Baseline Uganda Neuropsychological Test Battery Summary measure (U NP Sum) [4]
[units: z-scores]
Mean ± Standard Deviation
  -0.97  ± 0.78     -0.97  ± 0.86     -0.97  ± 0.82  
WHO-UCLA Auditory Verbal Learning Test (AVLT): Trials Total [5]
[units: z-scores]
Mean ± Standard Deviation
  -1.28  ± 0.88     -1.48  ± 1.14     -1.38  ± 1.02  
WHO-UCLA Auditory Verbal Learning Test (AVLT): Delayed [6]
[units: z-scores]
Mean ± Standard Deviation
  -1.17  ± 0.79     -1.15  ± 1.18     -1.16  ± 1.00  
Color Trails 1 [7]
[units: z-scores]
Mean ± Standard Deviation
  -1.35  ± 2.03     -1.65  ± 3.03     -1.51  ± 2.60  
Color Trails 2 [7]
[units: z-scores]
Mean ± Standard Deviation
  -2.55  ± 2.07     -2.33  ± 2.05     -2.44  ± 2.05  
Grooved Pegboard Dominant [8]
[units: z-scores]
Mean ± Standard Deviation
  -0.34  ± 1.58     -0.03  ± 1.14     -0.18  ± 1.37  
Grooved Pegboard Non-dominant [8]
[units: z-scores]
Mean ± Standard Deviation
  -0.56  ± 1.82     -0.48  ± 1.42     -0.52  ± 1.61  
Symbol Digit [9]
[units: z-scores]
Mean ± Standard Deviation
  -0.87  ± 0.96     -0.86  ± 0.80     -0.86  ± 0.88  
Digit Span Backward [10]
[units: z-scores]
Mean ± Standard Deviation
  -0.68  ± 0.75     -0.94  ± 1.06     -0.81  ± 0.93  
Digit Span Forward [10]
[units: z-scores]
Mean ± Standard Deviation
  0.02  ± 0.79     0.19  ± 0.99     0.11  ± 0.90  
[1]

The Memorial Sloan Kettering (MSK) clinical scale was defined below:

  • Stage 0: normal
  • Stage 0.5: equivocal/subclinical
  • Stage 1: mild
  • Stage 2: moderate
  • Stage 3: severe
  • Stage 4: end stage
[2] 100:Normal,90:normal;Minor Signs or Symptoms of Disease,80:Normal Activity with Effort;Some Signs or Symptoms of Disease,70:Cares for Self,Unable to Carry on Normal Activity or to Do Active Work,60:Requires Occasional Assistance but is Able to Care for Most of Needs,50:Requires Considerable Assistance and Frequent Medical Care,40:Disabled,Requires Special Care and Assistance,30:Severely Disabled; Hospitalization Indicated Although Death is Not Imminent,20:Very Sick; Hospitalization Necessary;Active Supportive Treatment is Necessary,10:Moribund, Fatal Processes Progressing Rapidly,0:Death
[3]

16 tasks: Housekeeping,Managing Finances,Buying Groceries,Cooking,Planning Social Activities,Understanding Reading Materials/TV,Transportation,Using the Telephone,Home Repairs,Bathing,Dressing,Shopping,Laundry,Taking/Keeping Track of Medication,Child Care,Work.

For the baseline IADL measure, participants were given four choices to choose for having difficulty on the 16 tasks:Primarily Cognitive problems,Primarily physical problems,equally cognitive and physical problems,not having any difficulties on previous tasks.

[4] Uganda Neuropsychological Test Battery Summary measure (U NP Sum)is the average z-scores of the 9 neurupsychological tests:Grooved Pegboard Dominant Hand,Grooved Pegboard Non-dominant Hand,Color Trail1,Color Trail2,Symbol Digit,WHO/UCLA Verbal Learning Test Trial 5,WHO/UCLA Verbal Learning Test Delayed Recall,Digit Span-Forward,Digit Span-Backward Since the score depends on age and education levels, the raw score was standardized as follows: Zx =(x − μx)/σx where Zx is the age and education adjusted z-score, x is the raw score, and μx and σx are the age and education stratified norms.
[5]

World Health Organization-University of California Los Angeles (WHO-UCLA) Auditory Verbal Learning Test (AVLT) is a full-scale memory assessment.

Since the score depends on age and education levels, the raw score was standardized as follows:

Zx =(x − μx)/σx where Zx is the age and education adjusted z-score, x is the raw score, and μx and σx are the age and education stratified norms.

[6]

World Health Organization-University of California Los Angeles (WHO-UCLA) Auditory Verbal Learning Test (AVLT) is a memory assessment.

Since the score depends on age and education levels, the raw score was standardized as follows:

Zx =(x − μx)/σx where Zx is the age and education adjusted z-score, x is the raw score, and μx and σx are the age and education stratified norms.

[7]

The Color Trails tests measure speed of attention, sequencing, mental flexibility, visual search, and motor function.

Since the score depends on age and education levels, the raw score was standardized as follows:

Zx =(x − μx)/σx where Zx is the age and education adjusted z-score, x is the raw score, and μx and σx are the age and education stratified norms.

[8]

The grooved pegboard is a manipulative dexterity test requiring rapid visual-motor coordination. The test is completed using the dominant hand (GPD) and then using the non-dominant hand (GPN). The score for each hand is the time in seconds that the participant takes to complete the entire board.

Since the score depends on age and education levels, the raw score was standardized as follows:

Zx =(x − μx)/σx where Zx is the age and education adjusted z-score, x is the raw score, and μx and σx are the age and education stratified norms.

[9]

This test assesses the participant's ability to maintain rapid visual-motor sequencing in a timed test. The score is the total number of correctly transcribed numbers in the time limit (90 seconds). Participants receive 1 point for each item filled in correctly. Maximum score is 110 points.

Since the score depends on age and education levels, the raw score was standardized as follows:

Zx =(x − μx)/σx where Zx is the age and education adjusted z-score, x is the raw score, and μx and σx are the age and education stratified norms.

[10]

Digit span assesses attention, concentration, and mental control(e.g., Repeat the numbers 1-2-3 in reverse sequence).

Since the score depends on age and education levels, the raw score was standardized as follows:

Zx =(x − μx)/σx where Zx is the age and education adjusted z-score, x is the raw score, and μx and σx are the age and education stratified norms.




  Outcome Measures
  Show All Outcome Measures

1.  Primary:   24-week Change of Uganda Neuropsychological Test Battery Summary Measure (U NP Sum)   [ Time Frame: At baseline and week 24 ]

2.  Secondary:   24-week Change of Memorial Sloan Kettering (MSK) HIV Dementia Stage   [ Time Frame: At baseline and week 24 ]

3.  Secondary:   24-week Change of Karnofsky Performance Score   [ Time Frame: At baseline and week 24 ]

4.  Secondary:   Time From Treatment Initiation to the Development of a Grade ≥ 2 Toxicity and/or Sign and Symptoms.   [ Time Frame: Time of initial Grade ≥ 2 toxicity and/or sign and symptom event up to week 24 ]

5.  Secondary:   Time From Treatment Initiation to the Development of a Grade ≥ 2 Toxicity and/or Sign and Symptoms   [ Time Frame: Time of first Grade ≥ 2 toxicity and/or sign and symptom event up to 48 weeks ]

6.  Secondary:   24-week Change of CD4 Cell Counts   [ Time Frame: At baseline and week 24 ]

7.  Secondary:   48-week Change of CD4 Cell Counts   [ Time Frame: At baseline and week 48 ]

8.  Secondary:   24-week Change of Instrumental Activities of Daily Living   [ Time Frame: At baseline and week 24 ]

9.  Secondary:   24-week Change of HIV RNA Plasma Viral Loads (Log10 Transformed)   [ Time Frame: At baseline and week 24 ]

10.  Secondary:   24-week Change of Center for Epidemiologic Studies Depression (CES-D) Score   [ Time Frame: At baseline and week 24 ]


  Serious Adverse Events


  Other Adverse Events


  Limitations and Caveats


  More Information