Minocycline for the Treatment of Decreased Mental Function in HIV-Infected Adults

This study has been terminated.
(This study was terminated early due to futility.)
Sponsor:
Collaborators:
Neurologic AIDS Research Consortium (NARC)
Information provided by:
AIDS Clinical Trials Group
ClinicalTrials.gov Identifier:
NCT00361257
First received: August 4, 2006
Last updated: June 27, 2011
Last verified: June 2011
Results First Received: January 28, 2011  
Study Type: Interventional
Study Design: Allocation: Randomized;   Endpoint Classification: Safety/Efficacy Study;   Intervention Model: Parallel Assignment;   Masking: Double Blind (Subject, Caregiver);   Primary Purpose: Treatment
Condition: HIV Infections
Interventions: Drug: Minocycline
Drug: Placebo (Tetracycline)

  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
No text entered.

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
Minocycline 100 mg orally every 12 hours
Matching Placebo Placebo taken orally every 12 hours

Participant Flow for 2 periods

Period 1:   Step 1: Minocycline vs. Placebo
    Minocycline     Matching Placebo  
STARTED     52     55  
COMPLETED     40     43  
NOT COMPLETED     12     12  

Period 2:   Step 2: Minocycline(Open Label) for All
    Minocycline     Matching Placebo  
STARTED     28 [1]   34 [2]
COMPLETED     13     19  
NOT COMPLETED     15     15  
[1] 40 participants completed Step 1; however,12 decided not to enroll Step 2,so 40-12=28 started Step 2
[2] 43 participants completed Step 1; however, 9 decided not to enroll Step 2,so 43-9=34 started Step 2.



  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 100 mg orally every 12 hours
Matching Placebo Placebo taken orally every 12 hours
Total Total of all reporting groups

Baseline Measures
    Minocycline     Matching Placebo     Total  
Number of Participants  
[units: participants]
  52     55     107  
Age  
[units: participants]
     
<=18 years     0     0     0  
Between 18 and 65 years     52     54     106  
>=65 years     0     1     1  
Age  
[units: years]
Mean ± Standard Deviation
  50  ± 7     52  ± 7     51  ± 7  
Gender  
[units: participants]
     
Female     5     13     18  
Male     47     42     89  
Cognitive Performance Score NPZ-8 [1]
[units: z-score]
Mean ± Standard Deviation
  -0.75  ± 0.90     -1.03  ± 0.98     -0.90  ± 0.95  
Global Deficit Z-Score (GDS) [2]
[units: z-score]
Mean ± Standard Deviation
  -0.86  ± 0.72     -1.08  ± 0.90     -0.97  ± 0.82  
Cognitive Gross Motor Function Domain Z-Score [3]
[units: z-score]
Mean ± Standard Deviation
  -2.44  ± 3.10     -3.66  ± 4.16     -3.06  ± 3.71  
Fine Motor Function Domain Z-Score [4]
[units: z-score]
Mean ± Standard Deviation
  -0.35  ± 0.96     -0.73  ± 0.99     -0.55  ± 0.99  
Psychomotor Function Domain Z-Score [5]
[units: z-score]
Mean ± Standard Deviation
  0.15  ± 1.00     0.04  ± 1.03     0.10  ± 1.01  
Fine Motor/Nonverbal Function Domain Z-Score [6]
[units: z-score]
Mean ± Standard Deviation
  -1.11  ± 1.15     -1.24  ± 1.18     -1.18  ± 1.16  
Information Processing Function Domain Z-Score [7]
[units: z-score]
Mean ± Standard Deviation
  -1.05  ± 1.52     -1.03  ± 1.49     -1.04  ± 1.50  
Verbal Memory Domain Z-Score [8]
[units: z-score]
Mean ± Standard Deviation
  -1.33  ± 1.16     -1.41  ± 1.12     -1.37  ± 1.14  
Frontal Systems Function Domain Z-Score [9]
[units: z-score]
Mean ± Standard Deviation
  -0.79  ± 0.98     -1.05  ± 1.57     -0.92  ± 1.32  
Karnofsky Score [10]
[units: participants]
     
70     5     0     5  
80     13     16     29  
90     21     34     55  
100     8     5     13  
missing     5     0     5  
Cluster of Differentiation 4 (CD4) [11]
[units: copies/mm^3]
Mean ± Standard Deviation
  551.65  ± 312.96     535.49  ± 253.11     543.35  ± 282.53  
Cluster of Differentiation 8 (CD8) [12]
[units: copies/mm^3]
Mean ± Standard Deviation
  925.58  ± 370.48     838.78  ± 353.73     880.96  ± 362.88  
HIV-1 Plasma RiboNucleic Acid (RNA) Viral Loads [13]
[units: participants]
     
Plasma RNA VL >=30 copies/mL     7     6     13  
Plasma RNA VL < 30 copies/mL     42     41     83  
missing     3     8     11  
HIV-1 CerebroSpinal Fluid (CSF) RNA Viral Loads (VL) [14]
[units: participants]
     
CSF RNA VL >=30 copies/mL     1     2     3  
CSF RNA VL <30 copies/mL     20     18     38  
missing     31     35     66  
Central Nervous System (CNS) Penetration Score [15]
[units: Scores on a scale]
Mean ± Standard Deviation
  7  ± 3     7  ± 3     7  ± 3  
Stratification Variable 1 - CSF Viral Load (VL) - Pre-baseline [16]
[units: participants]
     
CSF RNA VL < 30 copies/mL     21     22     43  
CSF RNA VL >= 30 copies/mL     3     4     7  
No Lumbar Punctures (LPs)     28     29     57  
Stratification Variable 2 - Objective or subjective Neuropsychological test - Pre-baseline [17]
[units: participants]
     
Objective Neuropsychological (NP) Test     5     7     12  
Subjective NP Test     47     48     95  
Instrumental Activities of Daily Living (IADL) Summary Score [18]
[units: Scores on a scale]
Mean ± Standard Deviation
  0.12  ± 0.15     0.13  ± 0.16     0.12  ± 0.15  
Medication Management Test (MMT) Score [19]
[units: Scores on a scale]
Mean ± Standard Deviation
  14.72  ± 1.41     14.09  ± 2.52     14.39  ± 2.08  
Alternate Psychomotor Function Z-Score [20]
[units: z-score]
Mean ± Standard Deviation
  -0.54  ± 0.82     -0.63  ± 0.92     -0.58  ± 0.87  
Alternate Verbal Memory Z-Score [21]
[units: z-score]
Mean ± Standard Deviation
  -1.33  ± 1.16     -1.41  ± 1.12     -1.37  ± 1.14  
Alternate Frontal Systems Z-Score [22]
[units: z-score]
Mean ± Standard Deviation
  -0.04  ± 0.86     -0.13  ± 1.09     -0.09  ± 0.98  
[1]

Cognitive performance is measured by NPZ-8. The NPZ-8 is defined as the average of age and education adjusted z-scores of eight neuropsychological tests subcomponents in the neuropsychological test battery:

  1. Grooved Pegboard Dominant Hand (GPD)
  2. Grooved Pegboard Non-dominant hand (GPN)
  3. Choice Reaction Time (CRT)
  4. Sequential Reaction Time (QRT)
  5. Timed Gait (TIG)
  6. Trail Making Part A (TMA)
  7. Trail Making Part B (TMB)
  8. Symbol Digit (SYD)
[2] GDS is defined as the average of age and education adjusted z-scores of 14 individual deficit scores in the test battery, including Time Gait, Grooved Pegboard Test for the dominant and non-dominant hands, Trail Making Test parts A and B, Symbol Digit Test, simple and sequential reaction time - CalCAP, Hopkins Verbal Learning Test (Revised)- Learning, Delayed Recall and Recognition trials, and Stroop Color Interference Test-color, word, and interference tasks.
[3] The cognitive gross motor function is age and education adjusted z-score of Timed Gait.
[4] This is an average z-scores of Grooved Pegboard Dominant and Non-Dominant Hand Tests adjusted for age, sex, education, and African-American ethnicity. 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.
[5] This is an average of z-scores of Trail Making Part A (TMA) and Trail Making Part B (TMB) tests adjusted for age, sex, education, and African-American ethnicity. The TMA and TMB tests are measures of planning ability, visual-motor speed and concentration. Subjects are required to connect randomly placed numbers in sequence (1-25 for TMA) or to sequentially connect both numbers and letters while alternating back and forth (1-A-2-B-3-C-4-D etc. for TMB). Scores are the time in seconds required to complete the tasks.
[6] This score is a age and education adjusted z score of Symbol Digit Test (SYD). 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.
[7] This is the average age and education adjusted z-scores of simple and sequential reaction time tests adjusted for age and education.
[8] This is the average of z-scores of Hopkins Verbal Learning Test- Revised, Learning and Delayed Recall Tests adjusted for age and education. The recognition test list comprises 24 words, consisting of 12 words from the original list and 12 "distracters". The subject must answer "yes" if the word was from the list and "no" otherwise. Twenty minutes after the third list from verbal learning and immediate recall, delayed recall is assessed by asking the subject to recall as many words as possible from the list. The score is the number of words that are correctly recalled from the original list.
[9] This is the average age and education adjusted z-scores of Stroop Color Interference Test (CTP) and interference task (STP). The Stroop Task is a measure of divided attentional abilities. Performance is measured by the amount of time required to read each of three cards: (1) blocks of colors, (2) names of colors, and (3) colored words. For each task, the time (in seconds) is the score that should be recorded on the form. A task that cannot be completed in 240 seconds is scored as incomplete.
[10]

Karnofsky performance score is ranged from 100 to 0:

100: Normal; 90: Able to Carry on normal Activity; 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; 10: Morbibund, Fatal Processes Progressing Rapidly; 0: Death

[11] CD4 counts by group at baseline
[12] CD8 counts by group at baseline
[13] HIV Plasma RNA viral load less than 30 copies/mL is undetectable, the values will be imputed as 30 copies/mL.
[14] HIV CSF RNA viral load less than 30 copies/mL is undetectable, the values will be imputed as 30 copies/mL.
[15] The baseline CNS penetration score is calculated based on the revised CNS penetration-effectiveness ranks (provided by Dr. Scott Letendre). The score is simply a sum of the ranks of all drugs which participants took at baseline. The better the drug penetrates, the higher the score. The range of ranks are 1 to 4, so the CNS penetration score is integer numbers greater than 1.
[16] Participants were stratified based on two factors. One is CSF HIV-1 RNA. This variable has three levels using the TaqMan assay in CSF: (1) HIV CSF RNA VLs ≥30 copies/mL (detectable), <30 copies/mL (Undetectable), or no lumbar punctures (LPs). The assessment was conducted BEFORE the baseline in order to use this information for randomization.
[17] The 2nd stratification factor is progressive neurocognitive decline defined by objective or subjective criteria at pre-baseline. A decline of at least 1.0 standard deviation below age-matched and education-matched controls on two or more independent tests or 2.0 standard deviations below age-matched and education-matched controls on one test within 1 year before entry is defined as objective decline. Otherwise, subjective neurocognitive decline is defined by the participant or family member or caregiver AND a Center for Epidemiological Studies Depression score <16 within 45 days before entry.
[18] The IADL questionnaire has 16 common tasks: 1. Housekeeping; 2.Managing Finances; 3. Buying Groceries; 4.Cooking; 5. Planning Social Activities; 6.Understanding Reading Materials/TV; 7.Transportation; 8.Using the Telephone; 9.Home Repairs; 10.Bathing; 11.Dressing; 12.Shopping; 13.Laundry; 14.Taking/Keeping Track of Medication; 15.Child Care; 16.Work. For each task, if the score at the time of evaluation is worse than the best in the past, an indicator of 1 is given; otherwise 0. The IADL score is a sum of 16 indicators divided by 16. The lower score indicates better. The range is from 0 to 1.
[19] The medication management test (modified) is designed to assess participants' medication management ability and their own medications and management. It’s the number of how many times participants correctly answered 16 questions.
[20] This is the average of z scores of Trail Making Part A and Symbol Digit Tests. Trail Making Part A z score was adjusted for age, sex, education, and African-Ametrican ethnicity. Symbol Digit z score was adjusted for age and education.
[21] This is the average of age and education adjusted z scores of standardized trials 1 to 3 and delayed recall tests.
[22] This is average of z scores of standardized interference task and trailmaking part b tests. The interference task z score was adjusted for age and education. The trailmaking part b z score was adjusted for age, sex, education, and African-American ethnicity.



  Outcome Measures
  Show All Outcome Measures

1.  Primary:   Change in Cognitive Performance Compared to Baseline   [ Time Frame: At baseline and week 24 ]

2.  Secondary:   Change in Global Deficit Z-Score (GDS)   [ Time Frame: At baseline and week 24 ]

3.  Secondary:   Change in Investigator's Clinical Global Impression Score (ICGIS)   [ Time Frame: At week 24 ]

4.  Secondary:   Change in Cognitive Gross Motor Function Domain Z-Score   [ Time Frame: At baseline and week 24 ]

5.  Secondary:   Change in Fine Motor Function Domain Z-Score   [ Time Frame: At baseline and week 24 ]

6.  Secondary:   Change in Psychomotor Function Domain Z-Score   [ Time Frame: At baseline and week 24 ]

7.  Secondary:   Change in Fine Motor/Nonverbal Function Domain Z-Score   [ Time Frame: At baseline and week 24 ]

8.  Secondary:   Change in Information Processing Function Domain Z-Score   [ Time Frame: At baseline and week 24 ]

9.  Secondary:   Change in Verbal Memory Domain Z-Score   [ Time Frame: At baseline and week 24 ]

10.  Secondary:   Change in Frontal Systems Function Domain Z-Score   [ Time Frame: At baseline and week 24 ]

11.  Secondary:   Change in Karnofsky Performance Score   [ Time Frame: At baseline and week 24 ]

12.  Secondary:   Changes in Cluster of Differentiation 4 (CD4) Cell Counts (24 Weeks)   [ Time Frame: At baseline and weeks 24 ]

13.  Secondary:   Changes in Cluster of Differentiation 8 (CD8) Cell Counts (24 Weeks)   [ Time Frame: At baseline and week 24 ]

14.  Secondary:   Number of Participants With Grade 2 or Higher Toxicity and/or Signs and Symptoms   [ Time Frame: Throughout study up to week 48 ]

15.  Secondary:   Change of HIV Plasma RiboNucleic Acid (RNA) Viral Load   [ Time Frame: At baseline and week 24 ]

16.  Secondary:   Changes in Instrumental Activities of Daily Living Questionnaire   [ Time Frame: At baseline and week 24 ]

17.  Secondary:   Changes in Medication Management Test (Modified)   [ Time Frame: At baseline and weeks 24 ]

18.  Secondary:   Changes in Alternate Psychomotor Function Z-Score   [ Time Frame: At baseline and week 24 ]

19.  Secondary:   Changes in Alternate Verbal Memory Z-Score   [ Time Frame: At baseline and week 24 ]

20.  Secondary:   Changes in Alternate Frontal Systems Z-Score   [ Time Frame: At baseline and week 24 ]

21.  Secondary:   Markers Including, But Not Limited to, Those of Immune Activation and Oxidative Stress/Apoptosis   [ Time Frame: At pre-entry and Week 24 ]
Results not yet posted.   Anticipated Posting Date:   06/2011   Safety Issue:   No


  Serious Adverse Events


  Other Adverse Events


  Limitations and Caveats
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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
Originally, 100 participants were expected to enroll. As of the early termination notice, 107 participants were randomized, yet not all subjects could complete the 24 week assessment.


  More Information
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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 less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.
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.


Results Point of Contact:  
Name/Title: Clinicaltrials.gov Coordinator
Organization: Center for Biostatistics in AIDS Research, Harvard School of Public Health
phone: (617) 432-2829
e-mail: CBAR.ClinicalTrials.Gov@sdac.harvard.edu


Publications:

Responsible Party: Daniel R. Kuritzkes, M.D., Social & Scientific Systems, Inc.
ClinicalTrials.gov Identifier: NCT00361257     History of Changes
Other Study ID Numbers: ACTG A5235, 1U01AI068636
Study First Received: August 4, 2006
Results First Received: January 28, 2011
Last Updated: June 27, 2011
Health Authority: United States: Food and Drug Administration