Minocycline for HIV+ Cognitive Impairment in Uganda
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Study Type:  Interventional 

Study Design:  Allocation: Randomized; Intervention Model: Single Group Assignment; Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor); Primary Purpose: Treatment 
Conditions: 
HIVassociated Cognitive Impairment HIV Infections 
Interventions: 
Drug: minocycline Drug: minocycline placebo capsule 
Participant Flow
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. 
PreAssignment 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
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  

Overall Participants Analyzed [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 (InterQuartile 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 ^{[1] } [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) ^{[1] } [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) ^{[1] } [Units: Zscores] Mean (Standard Deviation) 
0.97 (0.78)  0.97 (0.86)  0.97 (0.82)  


WHOUCLA Auditory Verbal Learning Test (AVLT): Trials Total ^{[1] } [Units: Zscores] Mean (Standard Deviation) 
1.28 (0.88)  1.48 (1.14)  1.38 (1.02)  


WHOUCLA Auditory Verbal Learning Test (AVLT): Delayed ^{[1] } [Units: Zscores] Mean (Standard Deviation) 
1.17 (0.79)  1.15 (1.18)  1.16 (1.00)  


Color Trails 1 ^{[1] } [Units: Zscores] Mean (Standard Deviation) 
1.35 (2.03)  1.65 (3.03)  1.51 (2.60)  


Color Trails 2 ^{[1] } [Units: Zscores] Mean (Standard Deviation) 
2.55 (2.07)  2.33 (2.05)  2.44 (2.05)  


Grooved Pegboard Dominant ^{[1] } [Units: Zscores] Mean (Standard Deviation) 
0.34 (1.58)  0.03 (1.14)  0.18 (1.37)  


Grooved Pegboard Nondominant ^{[1] } [Units: Zscores] Mean (Standard Deviation) 
0.56 (1.82)  0.48 (1.42)  0.52 (1.61)  


Symbol Digit ^{[1] } [Units: Zscores] Mean (Standard Deviation) 
0.87 (0.96)  0.86 (0.80)  0.86 (0.88)  


Digit Span Backward ^{[1] } [Units: Zscores] Mean (Standard Deviation) 
0.68 (0.75)  0.94 (1.06)  0.81 (0.93)  


Digit Span Forward ^{[1] } [Units: Zscores] Mean (Standard Deviation) 
0.02 (0.79)  0.19 (0.99)  0.11 (0.90)  

Outcome Measures
1. Primary:  24week Change of Uganda Neuropsychological Test Battery Summary Measure (U NP Sum) [ Time Frame: At baseline and week 24 ] 
2. Secondary:  24week Change of Memorial Sloan Kettering (MSK) HIV Dementia Stage [ Time Frame: At baseline and week 24 ] 
3. Secondary:  24week 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:  24week Change of CD4 Cell Counts [ Time Frame: At baseline and week 24 ] 
Measure Type  Secondary 

Measure Title  24week Change of CD4 Cell Counts 
Measure Description  The outcome is defined as CD4 cell count at week 24  CD4 cell count at baseline. The unit is cells/mm^3. 
Time Frame  At baseline and week 24 
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. 

This analysis used the participants with CD4 cell counts at baseline and week 24. 
Reporting Groups
Description  

Minocycline  Minocycline 100 mg orally every 12 hours 
Placebo  Placebo minocycline capsules every 12 hours 
Measured Values
Minocycline  Placebo  

Participants Analyzed [Units: Participants] 
29  28 
24week Change of CD4 Cell Counts [Units: Cells/mm^3] Mean (Standard Deviation) 
25.28 (70.85)  28.57 (61.65) 
Statistical Analysis 1 for 24week Change of CD4 Cell Counts
Groups ^{[1]}  All groups 

Statistical Test Type ^{[2]}  Superiority or Other 
Statistical Method ^{[3]}  Regression, Linear 
P Value ^{[4]}  0.647 
Mean Difference (Net) ^{[5]}  8.11 
95% Confidence Interval  27.23 to 43.45 
Standard Error of the mean  (17.63) 
[1]  Additional details about the analysis, such as null hypothesis and power calculation: 

The null hypothesis is that the mean 24week change of CD4 cell counts in the minocycline group is the same as the one in the placebo group.  
[2]  Details of power calculation, definition of noninferiority margin, and other key parameters: 
No text entered.  
[3]  Other relevant method information, such as adjustments or degrees of freedom: 
The model was adjusted for the baseline CD4 counts.  
[4]  Additional information, such as whether or not the pvalue is adjusted for multiple comparisons and the a priori threshold for statistical significance: 
The pvalue is not adjusted for multiple comparisons.  
[5]  Other relevant estimation information: 
No text entered. 
7. Secondary:  48week Change of CD4 Cell Counts [ Time Frame: At baseline and week 48 ] 
8. Secondary:  24week Change of Instrumental Activities of Daily Living [ Time Frame: At baseline and week 24 ] 
9. Secondary:  24week Change of HIV RNA Plasma Viral Loads (Log10 Transformed) [ Time Frame: At baseline and week 24 ] 
10. Secondary:  24week Change of Center for Epidemiologic Studies Depression (CESD) Score [ Time Frame: At baseline and week 24 ] 
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 

The estimated sample size was 100; however, due to early termination of the study, the total number of randomized participants was 73. 