Minocycline for HIV+ Cognitive Impairment in Uganda

• Sponsor: Johns Hopkins University (Other)
• Overall Status: Terminated
• CT.gov ID: NCT00855062
• Collaborator: Makerere University (Other)
• Enrollment: 73
• Location: 1
• Arms: 2
• Duration (Months): 20
• Patients Per Site Per Month: 3.6

Study Details

Study Description

Brief Summary

Purpose: The purpose of the study is to assess the safety and effectiveness of minocycline, an antibiotic, in the treatment of Human immunodeficiency virus (HIV)-associated cognitive impairment in Uganda.

Study Design: Treatment, 24-week Randomized, Placebo-Controlled, Double-Blind Phase with Optional 24-week Open Label Phase for Subjects with a cluster of differentiation 4 (CD4) Count in the 251-350 Range

• Arm 1: Minocycline 100 mg orally every 12 hours (50 subjects)

• Arm 2: Matching placebo orally every 12 hours (50 subjects)

Primary Objective:

· To examine whether minocycline treatment will improve cognitive performance after 24 weeks compared to baseline

Secondary Objectives:

• To examine whether minocycline treatment for 24 weeks is safe and well-tolerated in individuals with HIV-associated cognitive impairment

• To examine whether minocycline treatment for 48 weeks is safe and well-tolerated in individuals with HIV-associated cognitive impairment

• To examine whether minocycline treatment for 24 weeks improves functional impairment

Condition or Disease	Intervention/Treatment	Phase
HIV-associated Cognitive Impairment; HIV Infections	Drug: minocycline; Drug: minocycline placebo capsule	Phase 1/Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 73 participants
• Allocation: Randomized
• Intervention Model: Single Group Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Minocycline in the Treatment of HIV-Associated Cognitive Impairment in Uganda
• Study Start Date: Apr 1, 2008
• Actual Primary Completion Date: Dec 1, 2009
• Actual Study Completion Date: Dec 1, 2009

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Minocycline Minocycline 100 mg orally every 12 hours	Drug: minocycline; 100 mg capsule every 12 hours by mouth
Placebo Comparator: Placebo Placebo minocycline capsules every 12 hours	Drug: minocycline placebo capsule; 1 capsule every 12 hours by mouth

Outcome Measures

Primary Outcome Measures

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

   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.

Secondary Outcome Measures

1. 24-week Change of Memorial Sloan Kettering (MSK) HIV Dementia Stage [At baseline and week 24]

   The outcome is a new dichotomous variable: no change/worse vs. better at 24 weeks compared to baseline.

2. 24-week Change of Karnofsky Performance Score [At baseline and week 24]

   The outcome is a new dichotomous variable: no change/worse vs. better at 24 weeks compared to baseline.

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

   The outcome is the time to first Grade ≥ 2 toxicity and/or sign and symptoms from study treatment initiation up to week 24. The grade was determined by clinicians and an Grade ≥ 2 event means moderate, severe, life-threatening, or death event.

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

   The outcome is the time of first Grade ≥ 2 toxicity and/or sign and symptoms from treatment initiation up to 48 weeks. The grade was determined by clinicians and an Grade ≥ 2 event means moderate, severe, life-threatening, or death event.

5. 24-week Change of CD4 Cell Counts [At baseline and week 24]

   The outcome is defined as CD4 cell count at week 24 - CD4 cell count at baseline. The unit is cells/mm^3.

6. 48-week Change of CD4 Cell Counts [At baseline and week 48]

   The outcome is defined as CD4 cell count at week 48 - CD4 cell count at baseline. The unit is cells/mm^3.

7. 24-week Change of Instrumental Activities of Daily Living [At baseline and week 24]

   The outcome is a new dichotomous variable: no change/worse vs. better at 24 weeks compared to baseline.

8. 24-week Change of HIV RNA Plasma Viral Loads (Log10 Transformed) [At baseline and week 24]

   The outcome is the HIV RNA plasma viral loads (Log10 transformed) at week 24 - the viral loads (Log10 transformed) at baseline.

9. 24-week Change of Center for Epidemiologic Studies Depression (CES-D) Score [At baseline and week 24]

   The outcome is the total CES-D score at week 24 - the total CES-D score at baseline. The total CES-D score is based on 20 CES-D items, such as "I was bothered by things that usually don't bother me" and "I did not feel like eating, my appetite was poor". Patients were asked to answer each item by 4 scales: (1) Rarely, (2) Sometimes, (3) Occasionally, and (4) Most of the time. After 4 negative items were multiplied by -1, the total CES-D score is a simple sum of all items. The min and Max are 0 and 60, respectively. Higher scores indicate more severe depressive symptoms.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 65 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• HIV infection prior to study entry

• Naïve to any antiretroviral regimen and ineligible to receive antiretroviral therapy by cluster of differentiation 4 (CD4) criteria in Uganda

• Negative serum or urine pregnancy test for women of childbearing potential

• Willingness to use birth control

• Age 18-65 years

• AIDS Dementia Scale Stage 0.5 OR 1

• Impaired cognitive performance as evidenced by an International HIV Dementia Scale (HDS) as defined by the protocol

• Ability to sit or stand and swallow intact capsules with an 8-ounce glass of water

• Ability and willingness of subject or legal guardian/ representative to give written informed consent

• Resident within a 20km radius of Kampala city

Exclusion Criteria:

• Current cancers other than basal cell carcinoma, in situ carcinoma of the cervix, or Kaposi's sarcoma without evidence of visceral involvement or which does not require systemic chemotherapy

• Severe premorbid psychiatric illness, including schizophrenia and major depression which, in the in investigator's opinion, is likely to interfere with study compliance

• Active symptomatic AIDS-defining opportunistic infection within 45 days prior to study entry

• Confounding neurological disorders as defined in the protocol

• Central nervous system infections or cancers as defined in the protocol

• Systemic lupus

• Thyroid disease diagnosed within 24 weeks prior to entry

• Breastfeeding

• Active drug or alcohol use or dependence that, in the opinion of the investigator, would interfere with adherence to study requirements

• Serious illness requiring systemic treatment and/or hospitalization until subject either completes therapy or is clinically stable on therapy, in the opinion of the investigator

• History of allergy/sensitivity to minocycline or other tetracyclines and their formulations

• Any other clinically significant condition or laboratory abnormality that, in the opinion of the investigator, would interfere with the subject's ability to participate in the study. This includes an individual found to have an HIV dementia scale stage 3 or 4.

• Any esophageal or other condition that would interfere with the swallowing of the study medication

• Use of excluded drugs as defined by the protocol

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Infecious Diseas Institute	Kampala		Uganda

Sponsors and Collaborators

• Johns Hopkins University
• Makerere University

Investigators

• Principal Investigator: Ned Sacktor, MD, Johns Hopkins School of Medicine

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• ClinicalTrials.gov Identifier: NCT00855062
• Other Study ID Numbers: Uganda minocycline study; Grant Number: 5 UO1 NS32228
• First Posted: Mar 3, 2009
• Last Update Posted: Feb 25, 2011
• Last Verified: Jan 1, 2011

• Keywords provided by , ,: Human immunodeficiency virus (HIV); HIV associated cognitive impairment; HIV dementia; Uganda; Acquired immune deficiency syndrome (AIDS); Treatment Naive
• Additional relevant MeSH terms: Cognitive Dysfunction; Minocycline

Study Results

Participant Flow

Recruitment Details	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 Detail	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".

Arm/Group Title	Minocycline	Placebo
Arm/Group Description	Minocycline 100 mg orally every 12 hours	Placebo minocycline capsules every 12 hours
Period Title: Step1
STARTED	36	37
COMPLETED	26	26
NOT COMPLETED	10	11
Period Title: Step1
STARTED	19	21
COMPLETED	13	15
NOT COMPLETED	6	6

Baseline Characteristics

Arm/Group Title	Minocycline	Placebo	Total
Arm/Group Description	Minocycline 100 mg orally every 12 hours	Placebo minocycline capsules every 12 hours	Total of all reporting groups
Overall Participants	36	37	73
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	36 100%	37 100%	73 100%
>=65 years	0 0%	0 0%	0 0%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	37.3 (8.21)	36.7 (7.17)	37.0 (7.66)
Sex: Female, Male (Count of Participants)
Female	34 94.4%	32 86.5%	66 90.4%
Male	2 5.6%	5 13.5%	7 9.6%
Region of Enrollment (participants) [Number]
Uganda	36 100%	37 100%	73 100%
Baseline Memorial Sloan Kettering (MSK) Acquired Immune Deficiency Syndrome (AIDS) Dementia Scale (Number) [Number]
Equivocal/subclinical	35 97.2%	37 100%	72 98.6%
Mild	1 2.8%	0 0%	1 1.4%
Baseline Cluster of Differentiation Four (CD4) Count (cells/mm^3) [Median (Full Range) ]
Median (Full Range) [cells/mm^3]	319	305	313
Baseline Log10(Human immunodeficiency virus (HIV) Ribonucleic Acid (RNA) Viral Load (VL)) (copies/mL) [Log Mean (Inter-Quartile Range) ]
Log Mean (Inter-Quartile Range) [copies/mL]	4.41	4.59	4.50
Baseline Karnofsky's Performance Score (Number) [Number]
80 (Karnofsky Score)	1 2.8%	2 5.4%	3 4.1%
90 (Karnofsky Score)	35 97.2%	34 91.9%	69 94.5%
100 (Karnofsky Score)	0 0%	1 2.7%	1 1.4%
Baseline Instrumental Activities of Daily Living (IADL) (Number) [Number]
Primarily cognitive problems	1 2.8%	0 0%	1 1.4%
Primarily physical problems	6 16.7%	2 5.4%	8 11%
Not having any difficulties on the tasks	29 80.6%	35 94.6%	64 87.7%
Baseline Overall Neurological Assessment (Number) [Number]
Normal neurological assessment	26 72.2%	30 81.1%	56 76.7%
Central Nervous System (CNS) abnormality only	4 11.1%	5 13.5%	9 12.3%
Peripheral Nervous System (PNS) abnormality only	4 11.1%	1 2.7%	5 6.8%
CNS and PNS abnormality	1 2.8%	1 2.7%	2 2.7%
Can not assess	1 2.8%	0 0%	1 1.4%
Baseline Uganda Neuropsychological Test Battery Summary measure (U NP Sum) (z-scores) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [z-scores]	-0.97 (0.78)	-0.97 (0.86)	-0.97 (0.82)
WHO-UCLA Auditory Verbal Learning Test (AVLT): Trials Total (z-scores) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [z-scores]	-1.28 (0.88)	-1.48 (1.14)	-1.38 (1.02)
WHO-UCLA Auditory Verbal Learning Test (AVLT): Delayed (z-scores) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [z-scores]	-1.17 (0.79)	-1.15 (1.18)	-1.16 (1.00)
Color Trails 1 (z-scores) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [z-scores]	-1.35 (2.03)	-1.65 (3.03)	-1.51 (2.60)
Color Trails 2 (z-scores) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [z-scores]	-2.55 (2.07)	-2.33 (2.05)	-2.44 (2.05)
Grooved Pegboard Dominant (z-scores) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [z-scores]	-0.34 (1.58)	-0.03 (1.14)	-0.18 (1.37)
Grooved Pegboard Non-dominant (z-scores) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [z-scores]	-0.56 (1.82)	-0.48 (1.42)	-0.52 (1.61)
Symbol Digit (z-scores) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [z-scores]	-0.87 (0.96)	-0.86 (0.80)	-0.86 (0.88)
Digit Span Backward (z-scores) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [z-scores]	-0.68 (0.75)	-0.94 (1.06)	-0.81 (0.93)
Digit Span Forward (z-scores) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [z-scores]	0.02 (0.79)	0.19 (0.99)	0.11 (0.90)

Outcome Measures

1. Primary Outcome

Title	24-week Change of Uganda Neuropsychological Test Battery Summary Measure (U NP Sum)
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

Outcome Measure Data

Analysis Population Description

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).

Arm/Group Title	Minocycline	Placebo
Arm/Group Description	Minocycline 100 mg orally every 12 hours	Placebo minocycline capsules every 12 hours
Measure Participants	30	29
Mean (Standard Deviation) [z-score]	0.44 (0.74)	0.49 (0.67)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Minocycline, Placebo
	Comments	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.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.370
	Comments	The p-value was not adjusted for multiple comparisons.
	Method	Regression, Linear
	Comments
Method of Estimation	Estimation Parameter	Slope
	Estimated Value	-0.026
	Confidence Interval	(2-Sided) 95%; -0.512 to 0.460
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.248
	Estimation Comments

2. Secondary Outcome

Title	24-week Change of Memorial Sloan Kettering (MSK) HIV Dementia Stage
Description	The outcome is a new dichotomous variable: no change/worse vs. better at 24 weeks compared to baseline.
Time Frame	At baseline and week 24

Outcome Measure Data

Analysis Population Description

The descriptive statistics were based on observed data. Since all participants reported there were no change in the MSK score at week 24, no statistical test was conducted.

Arm/Group Title	Minocycline	Placebo
Arm/Group Description	Minocycline 100 mg orally every 12 hours	Placebo minocycline capsules every 12 hours
Measure Participants	28	27
No Change/Worse	28 77.8%	27 73%
Better	0 0%	0 0%

3. Secondary Outcome

Title	24-week Change of Karnofsky Performance Score
Description	The outcome is a new dichotomous variable: no change/worse vs. better at 24 weeks compared to baseline.
Time Frame	At baseline and week 24

Outcome Measure Data

Analysis Population Description

This analysis includes the participants with Karnofsky performance score at baseline and week 24.

Arm/Group Title	Minocycline	Placebo
Arm/Group Description	Minocycline 100 mg orally every 12 hours	Placebo minocycline capsules every 12 hours
Measure Participants	32	31
No Change/Worse	97 269.4%	94 254.1%
Better	3 8.3%	6 16.2%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Minocycline, Placebo
	Comments	The null hypothesis is that the percentage of participants feeling "better" in the minocycline group after 24 week treatment is the same as the one in the placebo group.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.613
	Comments	The p-value is not adjusted for multiple comparisons.
	Method	Fisher Exact
	Comments
Method of Estimation	Estimation Parameter	Median Difference (Net)
	Estimated Value	0.053
	Confidence Interval	(2-Sided) 95%; 0.043 to 0.062
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Secondary Outcome

Title	Time From Treatment Initiation to the Development of a Grade ≥ 2 Toxicity and/or Sign and Symptoms.
Description	The outcome is the time to first Grade ≥ 2 toxicity and/or sign and symptoms from study treatment initiation up to week 24. The grade was determined by clinicians and an Grade ≥ 2 event means moderate, severe, life-threatening, or death event.
Time Frame	Time of initial Grade ≥ 2 toxicity and/or sign and symptom event up to week 24

Outcome Measure Data

Analysis Population Description

This analysis includes every randomized participants. A total of 21 minocycline and 20 placebo participants reported at least one Grade ≥ 2 toxicity and/or sign and symptoms during 24 weeks

Arm/Group Title	Minocycline	Placebo
Arm/Group Description	Minocycline 100 mg orally every 12 hours	Placebo minocycline capsules every 12 hours
Measure Participants	36	37
0-4 weeks	12 33.3%	10 27%
4.01 - 12 weeks	6 16.7%	7 18.9%
12.01 - 24 weeks	3 8.3%	3 8.1%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Minocycline, Placebo
	Comments	The null hypothesis is that the survival curve for the first Grade ≥ 2 toxicity and/or sign and symptoms in the minocycline group is the same as the one in the placebo group.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.661
	Comments	The p-value is not adjusted for multiple comparisons.
	Method	Log Rank
	Comments

5. Secondary Outcome

Title	Time From Treatment Initiation to the Development of a Grade ≥ 2 Toxicity and/or Sign and Symptoms
Description	The outcome is the time of first Grade ≥ 2 toxicity and/or sign and symptoms from treatment initiation up to 48 weeks. The grade was determined by clinicians and an Grade ≥ 2 event means moderate, severe, life-threatening, or death event.
Time Frame	Time of first Grade ≥ 2 toxicity and/or sign and symptom event up to 48 weeks

Outcome Measure Data

Analysis Population Description

This analysis includes every randomized participants. A total of 22 minocycline and 21 placebo participants reported at least one Grade ≥ 2 toxicity and/or sign and symptoms during 48 weeks.

Arm/Group Title	Minocycline	Placebo
Arm/Group Description	Minocycline 100 mg orally every 12 hours	Placebo minocycline capsules every 12 hours
Measure Participants	36	37
0-4 weeks	12 33.3%	10 27%
4.01-12 weeks	6 16.7%	7 18.9%
12.01-24 weeks	3 8.3%	3 8.1%
24.01-48 weeks	1 2.8%	1 2.7%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Minocycline, Placebo
	Comments	The null hypothesis is that the 48-week survival curve for the first Grade ≥ 2 toxicity and/or sign and symptoms in the minocycline group is the same as the one in the placebo group.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.941
	Comments	The p-value is not adjusted for multiple comparisons.
	Method	Log Rank
	Comments

6. Secondary Outcome

Title	24-week Change of CD4 Cell Counts
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

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Minocycline	Placebo
Arm/Group Description	Minocycline 100 mg orally every 12 hours	Placebo minocycline capsules every 12 hours
Measure Participants	29	28
Mean (Standard Deviation) [cells/mm^3]	-25.28 (70.85)	-28.57 (61.65)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Minocycline, Placebo
	Comments	The null hypothesis is that the mean 24-week change of CD4 cell counts in the minocycline group is the same as the one in the placebo group.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.647
	Comments	The p-value is not adjusted for multiple comparisons.
	Method	Regression, Linear
	Comments	The model was adjusted for the baseline CD4 counts.
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	8.11
	Confidence Interval	(2-Sided) 95%; -27.23 to 43.45
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 17.63
	Estimation Comments

7. Secondary Outcome

Title	48-week Change of CD4 Cell Counts
Description	The outcome is defined as CD4 cell count at week 48 - CD4 cell count at baseline. The unit is cells/mm^3.
Time Frame	At baseline and week 48

Outcome Measure Data

Analysis Population Description

This analysis used the participants with CD4 cell counts at baseline and week 48.

Arm/Group Title	Minocycline	Placebo
Arm/Group Description	Minocycline 100 mg orally every 12 hours	Placebo minocycline capsules every 12 hours
Measure Participants	13	16
Mean (Standard Deviation) [cells/mm^3]	-61.15 (80.46)	-56.50 (84.97)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Minocycline, Placebo
	Comments	The null hypothesis is that the mean 48-week change in CD4 cell counts in the minocycline group is the same as the one in the placebo group.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.813
	Comments	The p-value was not adjusted for multiple comparisons.
	Method	Regression, Linear
	Comments	The model was adjusted for the baseline CD4 counts.
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	7.77
	Confidence Interval	(2-Sided) 95%; -59.07 to 74.60
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 32.51
	Estimation Comments

8. Secondary Outcome

Title	24-week Change of Instrumental Activities of Daily Living
Description	The outcome is a new dichotomous variable: no change/worse vs. better at 24 weeks compared to baseline.
Time Frame	At baseline and week 24

Outcome Measure Data

Analysis Population Description

The analysis includes participants with IADL scores at baseline and week 24.

Arm/Group Title	Minocycline	Placebo
Arm/Group Description	Minocycline 100 mg orally every 12 hours	Placebo minocycline capsules every 12 hours
Measure Participants	28	26
No Change/Worse	86 238.9%	88 237.8%
Better	14 38.9%	12 32.4%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Minocycline, Placebo
	Comments	The null hypothesis is that the percentage of being "better" at week 24 compared to baseline in the minocycline group is the same as the one in the placebo group.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.764
	Comments	The p-value is not adjusted for multiple comparisons.
	Method	Regression, Logistic
	Comments	The model was not adjusted for any covariate (due to small number of being "better" in both groups.
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.28
	Confidence Interval	() 95%; 0.26 to 6.34
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.82
	Estimation Comments

9. Secondary Outcome

Title	24-week Change of HIV RNA Plasma Viral Loads (Log10 Transformed)
Description	The outcome is the HIV RNA plasma viral loads (Log10 transformed) at week 24 - the viral loads (Log10 transformed) at baseline.
Time Frame	At baseline and week 24

Outcome Measure Data

Analysis Population Description

The analysis includes participants with HIV RNA viral loads at baseline and week 24.

Arm/Group Title	Minocycline	Placebo
Arm/Group Description	Minocycline 100 mg orally every 12 hours	Placebo minocycline capsules every 12 hours
Measure Participants	22	25
Median (Inter-Quartile Range) [copies/mL]	0.22	0.13

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Minocycline, Placebo
	Comments	The null hypothesis is that the median log10-transformed HIV RNA viral loads in the minocycline group is the same as the one in the placebo group.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.766
	Comments	The p-value is not adjusted for multiple comparisons.
	Method	Kruskal-Wallis
	Comments	The chi-square score was 0.024 and the degree of freedom was 1.

10. Secondary Outcome

Title	24-week Change of Center for Epidemiologic Studies Depression (CES-D) Score
Description	The outcome is the total CES-D score at week 24 - the total CES-D score at baseline. The total CES-D score is based on 20 CES-D items, such as "I was bothered by things that usually don't bother me" and "I did not feel like eating, my appetite was poor". Patients were asked to answer each item by 4 scales: (1) Rarely, (2) Sometimes, (3) Occasionally, and (4) Most of the time. After 4 negative items were multiplied by -1, the total CES-D score is a simple sum of all items. The min and Max are 0 and 60, respectively. Higher scores indicate more severe depressive symptoms.
Time Frame	At baseline and week 24

Outcome Measure Data

Analysis Population Description

The analysis includes participants with CES-D scores at baseline and week 24.

Arm/Group Title	Minocycline	Placebo
Arm/Group Description	Minocycline 100 mg orally every 12 hours	Placebo minocycline capsules every 12 hours
Measure Participants	31	28
Mean (Standard Deviation) [scores on a scale]	-4.19 (10.86)	-4.04 (8.27)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Minocycline, Placebo
	Comments	The null hypothesis is that the mean 24-week change of CES-D score in the minocycline group is the same as the one in the placebo group.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.915
	Comments	The p-value is not adjusted for multiple comparisons.
	Method	Regression, Linear
	Comments	The model was adjusted for the baseline CES-D and MSK scores.
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.19
	Confidence Interval	(2-Sided) 95%; -3.40 to 3.78
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.79
	Estimation Comments

Adverse Events

Time Frame	48 weeks
Adverse Event Reporting Description	The lab assessments were conducted at weeks 0, 12, 24, and 48.
Arm/Group Title	Minocycline		Placebo
Arm/Group Description	Minocycline 100 mg orally every 12 hours		Placebo minocycline capsules every 12 hours
All Cause Mortality
	Minocycline		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Minocycline		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/36 (5.6%)		1/37 (2.7%)
Hepatobiliary disorders
Sgpt	0/36 (0%)	0	1/37 (2.7%)	1
Sgot	0/36 (0%)	0	1/37 (2.7%)	1
Infections and infestations
Death	1/36 (2.8%)	1	0/37 (0%)	0
Renal and urinary disorders
Potassium	1/36 (2.8%)	1	0/37 (0%)	0
Other (Not Including Serious) Adverse Events
	Minocycline		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	26/36 (72.2%)		25/37 (67.6%)
Blood and lymphatic system disorders
Absolute Neutrophil Count	12/36 (33.3%)	21	12/37 (32.4%)	12
White Blood Cells	0/36 (0%)	0	2/37 (5.4%)	2
General disorders
Fever	2/36 (5.6%)	2	1/37 (2.7%)	1
Carbon Dioxide	4/36 (11.1%)	4	2/37 (5.4%)	2
Hepatobiliary disorders
SGOT	3/36 (8.3%)	3	0/37 (0%)	0
Renal and urinary disorders
Phosphorus	3/36 (8.3%)	3	3/37 (8.1%)	3
Sodium	2/36 (5.6%)	2	1/37 (2.7%)	1
Skin and subcutaneous tissue disorders
Allergic Rash	0/36 (0%)	0	4/37 (10.8%)	4

Limitations/Caveats

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

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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.