Minocycline for HIV+ Cognitive Impairment in Uganda

Study Overview
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Brief Summary
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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

Official Title
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Minocycline in the Treatment of HIV-Associated Cognitive Impairment in Uganda

Conditions
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HIV-associated Cognitive Impairment, HIV Infections

Intervention / Treatment
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* Drug: minocycline
* Drug: minocycline placebo capsule


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Single Group Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Minocycline<br>Minocycline 100 mg orally every 12 hours | Drug: minocycline<br>* 100 mg capsule every 12 hours by mouth<br>|
| Placebo Comparator: Placebo<br>Placebo minocycline capsules every 12 hours | Drug: minocycline placebo capsule<br>* 1 capsule every 12 hours by mouth<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 24-week Change of Uganda Neuropsychological Test Battery Summary Measure (U NP Sum) | 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. | At baseline and week 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 24-week Change of Memorial Sloan Kettering (MSK) HIV Dementia Stage | The outcome is a new dichotomous variable: no change/worse vs. better at 24 weeks compared to baseline. | At baseline and week 24 | 
| 24-week Change of Karnofsky Performance Score | The outcome is a new dichotomous variable: no change/worse vs. better at 24 weeks compared to baseline. | At baseline and week 24 | 
| Time From Treatment Initiation to the Development of a Grade ≥ 2 Toxicity and/or Sign and Symptoms. | 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 of initial Grade ≥ 2 toxicity and/or sign and symptom event up to week 24 | 
| Time From Treatment Initiation to the Development of a Grade ≥ 2 Toxicity and/or Sign and Symptoms | 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 of first Grade ≥ 2 toxicity and/or sign and symptom event up to 48 weeks | 
| 24-week Change of CD4 Cell Counts | The outcome is defined as CD4 cell count at week 24 - CD4 cell count at baseline. The unit is cells/mm^3. | At baseline and week 24 | 
| 48-week Change of CD4 Cell Counts | The outcome is defined as CD4 cell count at week 48 - CD4 cell count at baseline. The unit is cells/mm^3. | At baseline and week 48 | 
| 24-week Change of Instrumental Activities of Daily Living | The outcome is a new dichotomous variable: no change/worse vs. better at 24 weeks compared to baseline. | At baseline and week 24 | 
| 24-week Change of HIV RNA Plasma Viral Loads (Log10 Transformed) | The outcome is the HIV RNA plasma viral loads (Log10 transformed) at week 24 - the viral loads (Log10 transformed) at baseline. | At baseline and week 24 | 
| 24-week Change of Center for Epidemiologic Studies Depression (CES-D) Score | 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. | At baseline and week 24 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Human immunodeficiency virus (HIV), HIV associated cognitive impairment, HIV dementia, Uganda, Acquired immune deficiency syndrome (AIDS), Treatment Naive