Trial Outcomes & Findings for Minocycline for HIV+ Cognitive Impairment in Uganda (NCT NCT00855062)

Last Updated: 2011-02-25

Results Overview

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.

Recruitment status

TERMINATED

Study phase

PHASE1/PHASE2

Target enrollment

73 participants

Primary outcome timeframe

At baseline and week 24

Results posted on

2011-02-25

Participant Flow

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.

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".

Participant milestones

Participant milestones
Measure	Minocycline Minocycline 100 mg orally every 12 hours	Placebo Placebo minocycline capsules every 12 hours
Step1 STARTED	36	37
Step1 COMPLETED	26	26
Step1 NOT COMPLETED	10	11
Step2 STARTED	19	21
Step2 COMPLETED	13	15
Step2 NOT COMPLETED	6	6

Reasons for withdrawal

Reasons for withdrawal
Measure	Minocycline Minocycline 100 mg orally every 12 hours	Placebo Placebo minocycline capsules every 12 hours
Step1 Early Study Closure	5	7
Step1 Adverse Event	1	1
Step1 Protocol Violation	1	0
Step1 Pregnancy	1	0
Step1 Withdrawal by Subject	2	3
Step2 Early Study Closure	6	2
Step2 Adverse Event	0	3
Step2 Initiation of antiretroviral therapy/ART	0	1

Baseline Characteristics

Minocycline for HIV+ Cognitive Impairment in Uganda

Baseline characteristics by cohort

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

PRIMARY outcome

Timeframe: At baseline and week 24

Population: 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).

Outcome measures

Outcome measures
Measure	Minocycline n=30 Participants Minocycline 100 mg orally every 12 hours	Placebo n=29 Participants Placebo minocycline capsules every 12 hours
24-week Change of Uganda Neuropsychological Test Battery Summary Measure (U NP Sum)	0.44 z-score Standard Deviation 0.74	0.49 z-score Standard Deviation 0.67

SECONDARY outcome

Timeframe: At baseline and week 24

Population: 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.

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

Outcome measures

Outcome measures
Measure	Minocycline n=28 Participants Minocycline 100 mg orally every 12 hours	Placebo n=27 Participants Placebo minocycline capsules every 12 hours
24-week Change of Memorial Sloan Kettering (MSK) HIV Dementia Stage No Change/Worse	28 participants	27 participants
24-week Change of Memorial Sloan Kettering (MSK) HIV Dementia Stage Better	0 participants	0 participants

SECONDARY outcome

Timeframe: At baseline and week 24

Population: This analysis includes the participants with 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.

Outcome measures

Outcome measures
Measure	Minocycline n=32 Participants Minocycline 100 mg orally every 12 hours	Placebo n=31 Participants Placebo minocycline capsules every 12 hours
24-week Change of Karnofsky Performance Score No Change/Worse	97 percentage of participants	94 percentage of participants
24-week Change of Karnofsky Performance Score Better	3 percentage of participants	6 percentage of participants

SECONDARY outcome

Timeframe: Time of initial Grade ≥ 2 toxicity and/or sign and symptom event up to week 24

Population: 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

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.

Outcome measures

Outcome measures
Measure	Minocycline n=36 Participants Minocycline 100 mg orally every 12 hours	Placebo n=37 Participants Placebo minocycline capsules every 12 hours
Time From Treatment Initiation to the Development of a Grade ≥ 2 Toxicity and/or Sign and Symptoms. 0-4 weeks	12 participants with an event	10 participants with an event
Time From Treatment Initiation to the Development of a Grade ≥ 2 Toxicity and/or Sign and Symptoms. 4.01 - 12 weeks	6 participants with an event	7 participants with an event
Time From Treatment Initiation to the Development of a Grade ≥ 2 Toxicity and/or Sign and Symptoms. 12.01 - 24 weeks	3 participants with an event	3 participants with an event

SECONDARY outcome

Timeframe: Time of first Grade ≥ 2 toxicity and/or sign and symptom event up to 48 weeks

Population: 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.

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.

Outcome measures

Outcome measures
Measure	Minocycline n=36 Participants Minocycline 100 mg orally every 12 hours	Placebo n=37 Participants Placebo minocycline capsules every 12 hours
Time From Treatment Initiation to the Development of a Grade ≥ 2 Toxicity and/or Sign and Symptoms 0-4 weeks	12 participants with an event	10 participants with an event
Time From Treatment Initiation to the Development of a Grade ≥ 2 Toxicity and/or Sign and Symptoms 4.01-12 weeks	6 participants with an event	7 participants with an event
Time From Treatment Initiation to the Development of a Grade ≥ 2 Toxicity and/or Sign and Symptoms 12.01-24 weeks	3 participants with an event	3 participants with an event
Time From Treatment Initiation to the Development of a Grade ≥ 2 Toxicity and/or Sign and Symptoms 24.01-48 weeks	1 participants with an event	1 participants with an event

SECONDARY outcome

Timeframe: At baseline and week 24

Population: This analysis used the participants with 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.

Outcome measures

Outcome measures
Measure	Minocycline n=29 Participants Minocycline 100 mg orally every 12 hours	Placebo n=28 Participants Placebo minocycline capsules every 12 hours
24-week Change of CD4 Cell Counts	-25.28 cells/mm^3 Standard Deviation 70.85	-28.57 cells/mm^3 Standard Deviation 61.65

SECONDARY outcome

Timeframe: At baseline and week 48

Population: This analysis used the participants with 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.

Outcome measures

Outcome measures
Measure	Minocycline n=13 Participants Minocycline 100 mg orally every 12 hours	Placebo n=16 Participants Placebo minocycline capsules every 12 hours
48-week Change of CD4 Cell Counts	-61.15 cells/mm^3 Standard Deviation 80.46	-56.50 cells/mm^3 Standard Deviation 84.97

SECONDARY outcome

Timeframe: At baseline and week 24

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

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

Outcome measures

Outcome measures
Measure	Minocycline n=28 Participants Minocycline 100 mg orally every 12 hours	Placebo n=26 Participants Placebo minocycline capsules every 12 hours
24-week Change of Instrumental Activities of Daily Living No Change/Worse	86 percentage of participants	88 percentage of participants
24-week Change of Instrumental Activities of Daily Living Better	14 percentage of participants	12 percentage of participants

SECONDARY outcome

Timeframe: At baseline and week 24

Population: The analysis includes participants with HIV RNA viral loads 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.

Outcome measures

Outcome measures
Measure	Minocycline n=22 Participants Minocycline 100 mg orally every 12 hours	Placebo n=25 Participants Placebo minocycline capsules every 12 hours
24-week Change of HIV RNA Plasma Viral Loads (Log10 Transformed)	0.22 copies/mL Interval -0.14 to 0.5	0.13 copies/mL Interval -0.23 to 0.43

SECONDARY outcome

Timeframe: At baseline and week 24

Population: The analysis includes participants with CES-D scores 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.

Outcome measures

Outcome measures
Measure	Minocycline n=31 Participants Minocycline 100 mg orally every 12 hours	Placebo n=28 Participants Placebo minocycline capsules every 12 hours
24-week Change of Center for Epidemiologic Studies Depression (CES-D) Score	-4.19 scores on a scale Standard Deviation 10.86	-4.04 scores on a scale Standard Deviation 8.27

Adverse Events

Minocycline

Serious events: 2 serious events

Other events: 26 other events

Deaths: 0 deaths

Placebo

Serious events: 1 serious events

Other events: 25 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	Minocycline n=36 participants at risk Minocycline 100 mg orally every 12 hours	Placebo n=37 participants at risk Placebo minocycline capsules every 12 hours
Infections and infestations Death	2.8% 1/36 • Number of events 1 • 48 weeks The lab assessments were conducted at weeks 0, 12, 24, and 48.	0.00% 0/37 • 48 weeks The lab assessments were conducted at weeks 0, 12, 24, and 48.
Renal and urinary disorders Potassium	2.8% 1/36 • Number of events 1 • 48 weeks The lab assessments were conducted at weeks 0, 12, 24, and 48.	0.00% 0/37 • 48 weeks The lab assessments were conducted at weeks 0, 12, 24, and 48.
Hepatobiliary disorders Sgpt	0.00% 0/36 • 48 weeks The lab assessments were conducted at weeks 0, 12, 24, and 48.	2.7% 1/37 • Number of events 1 • 48 weeks The lab assessments were conducted at weeks 0, 12, 24, and 48.
Hepatobiliary disorders Sgot	0.00% 0/36 • 48 weeks The lab assessments were conducted at weeks 0, 12, 24, and 48.	2.7% 1/37 • Number of events 1 • 48 weeks The lab assessments were conducted at weeks 0, 12, 24, and 48.

Other adverse events

Other adverse events
Measure	Minocycline n=36 participants at risk Minocycline 100 mg orally every 12 hours	Placebo n=37 participants at risk Placebo minocycline capsules every 12 hours
General disorders Fever	5.6% 2/36 • Number of events 2 • 48 weeks The lab assessments were conducted at weeks 0, 12, 24, and 48.	2.7% 1/37 • Number of events 1 • 48 weeks The lab assessments were conducted at weeks 0, 12, 24, and 48.
Skin and subcutaneous tissue disorders Allergic Rash	0.00% 0/36 • 48 weeks The lab assessments were conducted at weeks 0, 12, 24, and 48.	10.8% 4/37 • Number of events 4 • 48 weeks The lab assessments were conducted at weeks 0, 12, 24, and 48.
General disorders Carbon Dioxide	11.1% 4/36 • Number of events 4 • 48 weeks The lab assessments were conducted at weeks 0, 12, 24, and 48.	5.4% 2/37 • Number of events 2 • 48 weeks The lab assessments were conducted at weeks 0, 12, 24, and 48.
Renal and urinary disorders Phosphorus	8.3% 3/36 • Number of events 3 • 48 weeks The lab assessments were conducted at weeks 0, 12, 24, and 48.	8.1% 3/37 • Number of events 3 • 48 weeks The lab assessments were conducted at weeks 0, 12, 24, and 48.
Renal and urinary disorders Sodium	5.6% 2/36 • Number of events 2 • 48 weeks The lab assessments were conducted at weeks 0, 12, 24, and 48.	2.7% 1/37 • Number of events 1 • 48 weeks The lab assessments were conducted at weeks 0, 12, 24, and 48.
Blood and lymphatic system disorders Absolute Neutrophil Count	33.3% 12/36 • Number of events 21 • 48 weeks The lab assessments were conducted at weeks 0, 12, 24, and 48.	32.4% 12/37 • Number of events 12 • 48 weeks The lab assessments were conducted at weeks 0, 12, 24, and 48.
Hepatobiliary disorders SGOT	8.3% 3/36 • Number of events 3 • 48 weeks The lab assessments were conducted at weeks 0, 12, 24, and 48.	0.00% 0/37 • 48 weeks The lab assessments were conducted at weeks 0, 12, 24, and 48.
Blood and lymphatic system disorders White Blood Cells	0.00% 0/36 • 48 weeks The lab assessments were conducted at weeks 0, 12, 24, and 48.	5.4% 2/37 • Number of events 2 • 48 weeks The lab assessments were conducted at weeks 0, 12, 24, and 48.

Additional Information

Sachiko Miyahara

Harvard School of Public Health

Phone: 617-432-2837

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place