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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
History of Changes
Results First Received: December 17, 2010  
Study Type: Interventional
Study Design: Allocation: Randomized;   Intervention Model: Single Group Assignment;   Masking: Double Blind (Participant, Care Provider, Investigator, Outcomes Assessor);   Primary Purpose: Treatment
Conditions: HIV-associated Cognitive Impairment
HIV Infections
Interventions: Drug: minocycline
Drug: minocycline placebo capsule

  Participant Flow
  Hide 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.

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
  Hide 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 
[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
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 [1] 
[Units: Participants]
 		     
80 (Karnofsky Score)   1   2   3 
90 (Karnofsky Score)   35   34   69 
100 (Karnofsky Score)   0   1   1 
[1] 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
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 
[1]

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.
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: Z-scores]
Mean (Standard Deviation) 		 -0.97  (0.78)   -0.97  (0.86)   -0.97  (0.82) 
[1] 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.
WHO-UCLA Auditory Verbal Learning Test (AVLT): Trials Total [1] 
[Units: Z-scores]
Mean (Standard Deviation) 		 -1.28  (0.88)   -1.48  (1.14)   -1.38  (1.02) 
[1]

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.
WHO-UCLA Auditory Verbal Learning Test (AVLT): Delayed [1] 
[Units: Z-scores]
Mean (Standard Deviation) 		 -1.17  (0.79)   -1.15  (1.18)   -1.16  (1.00) 
[1]

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.
Color Trails 1 [1] 
[Units: Z-scores]
Mean (Standard Deviation) 		 -1.35  (2.03)   -1.65  (3.03)   -1.51  (2.60) 
[1]

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.
Color Trails 2 [1] 
[Units: Z-scores]
Mean (Standard Deviation) 		 -2.55  (2.07)   -2.33  (2.05)   -2.44  (2.05) 
[1]

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.
Grooved Pegboard Dominant [1] 
[Units: Z-scores]
Mean (Standard Deviation) 		 -0.34  (1.58)   -0.03  (1.14)   -0.18  (1.37) 
[1]

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.
Grooved Pegboard Non-dominant [1] 
[Units: Z-scores]
Mean (Standard Deviation) 		 -0.56  (1.82)   -0.48  (1.42)   -0.52  (1.61) 
[1]

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.
Symbol Digit [1] 
[Units: Z-scores]
Mean (Standard Deviation) 		 -0.87  (0.96)   -0.86  (0.80)   -0.86  (0.88) 
[1]

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.
Digit Span Backward [1] 
[Units: Z-scores]
Mean (Standard Deviation) 		 -0.68  (0.75)   -0.94  (1.06)   -0.81  (0.93) 
[1]

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.
Digit Span Forward [1] 
[Units: Z-scores]
Mean (Standard Deviation) 		 0.02  (0.79)   0.19  (0.99)   0.11  (0.90) 
[1]

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 ]
  Hide Outcome Measure 1

Measure Type Primary
Measure Title 24-week Change of Uganda Neuropsychological Test Battery Summary Measure (U NP Sum)
Measure Description The U NP Sum is defined as the average of z scores for 9 neuropsychological test subcomponents in the neuropsychological test battery (i.e. the average of norm-adjusted ("z") scores for Grooved Pegboard Dominant Hand, Grooved Pegboard Non-dominant Hand, Color Trails 1, Color Trails 2, Symbol Digit, WHO-UCLA Verbal Learning test Trial 5, WHO-UCLA Verbal Learning test delayed recall, Digit Span forward and Digit Span backward). The outcome is defined as U NP Sum at week 24 - U NP Sum at baseline.
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.
The descriptive statistics are based on per protocol analysis. For the statistical analysis, ITT analysis was used and the missing U NP Sums at week 24 were imputed using a multiple regression imputation method. The number of participants analyzed for the ITT analysis was 73 (36 for Minocycline and 37 for Placebo).

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]
 		 30   29 
24-week Change of Uganda Neuropsychological Test Battery Summary Measure (U NP Sum) 
[Units: Z-score]
Mean (Standard Deviation) 		 0.44  (0.74)   0.49  (0.67) 


Statistical Analysis 1 for 24-week Change of Uganda Neuropsychological Test Battery Summary Measure (U NP Sum)
Groups [1] All groups
Statistical Test Type [2] Superiority or Other
Statistical Method [3] Regression, Linear
P Value [4] 0.370
Slope [5] -0.026
95% Confidence Interval -0.512 to 0.460
Standard Error of the mean (0.248)
[1] Additional details about the analysis, such as null hypothesis and power calculation:
 

The null hypothesis was that the 24-week changes of U NP Sum between the minocycline and placebo groups are the same.

The sample size calculation showed that 100 (50 participants in each group) were required to detect the clinically meaningful difference of 0.5 with 85% power, 0.05 Type I error, two-sample and two-sided test.
[2] Details of power calculation, definition of non-inferiority margin, and other key parameters:
  No text entered.
[3] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[4] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  The p-value was not adjusted for multiple comparisons.
[5] Other relevant estimation information:
  No text entered.



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

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

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 ]
  Show Outcome Measure 4

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 ]
  Show Outcome Measure 5

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

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

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

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

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


  Serious Adverse Events
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  Other Adverse Events
  Show Other Adverse Events


  Limitations and Caveats
  Hide 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.


  More Information
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Certain Agreements:  
Principal Investigators are NOT employed by the organization sponsoring the study.
There is NOT 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.


Results Point of Contact:  
Name/Title: Sachiko Miyahara
Organization: Harvard School of Public Health
phone: 617-432-2837
e-mail: miyahara@sdac.harvard.edu



Responsible Party: Ned Sacktor, MD, Johns Hopkins School of Medicine
ClinicalTrials.gov Identifier: NCT00855062     History of Changes
Other Study ID Numbers: Uganda minocycline study
Grant Number: 5 UO1 NS32228
Study First Received: March 2, 2009
Results First Received: December 17, 2010
Last Updated: January 28, 2011