Minocycline for HIV+ Cognitive Impairment in Uganda

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ClinicalTrials.gov Identifier: NCT00855062

Recruitment Status : 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.)

First Posted : March 3, 2009

Results First Posted : February 25, 2011

Last Update Posted : February 25, 2011

Sponsor:

Collaborator:

Makerere University

Information provided by:

Johns Hopkins University

Study Type:	Interventional
Study Design:	Allocation: Randomized; Intervention Model: Single Group Assignment; Masking: Quadruple (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

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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

Overall Participants Analyzed
[Units: Participants]

Age
[Units: Participants]

<=18 years

Between 18 and 65 years

>=65 years

Age
[Units: Years]
Mean (Standard Deviation)

37.3 (8.21)

36.7 (7.17)

37.0 (7.66)

Gender
[Units: Participants]

Female

Male

Region of Enrollment
[Units: Participants]

Uganda

Baseline Memorial Sloan Kettering (MSK) Acquired Immune Deficiency Syndrome (AIDS) Dementia Scale ^[1]
[Units: Participants]

Equivocal/subclinical

Mild

^[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)

90 (Karnofsky Score)

100 (Karnofsky Score)

^[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

Primarily physical problems

Not having any difficulties on the tasks

^[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

Central Nervous System (CNS) abnormality only

Peripheral Nervous System (PNS) abnormality only

CNS and PNS abnormality

Can not assess

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]

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

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1. Primary:

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

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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 ]

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3. Secondary:

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

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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 ]

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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 ]

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6. Secondary:

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

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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

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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
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
First Submitted:	March 2, 2009
First Posted:	March 3, 2009
Results First Submitted:	December 17, 2010
Results First Posted:	February 25, 2011
Last Update Posted:	February 25, 2011

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