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

Study Overview
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Brief Summary
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The purpose of this study is to determine the effectiveness of minocycline, an antibiotic, in lessening the decreased mental function sometimes caused by anti-HIV drugs.

Detailed Description
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Cognitive impairment, including disabling cognitive, behavioral, and social dysfunction, continues to be a major problem faced by HIV-infected people taking antiretroviral therapy (ART). Research is needed to develop treatment that can be given alongside ART to prevent or lessen cognitive impairment caused by ART. Minocycline, an antibiotic commonly used for the treatment of acne and rheumatoid arthritis, has demonstrated anti-inflammatory and neuroprotective properties in previous studies. This study will evaluate the effectiveness of 24-week therapy with minocycline in lessening the cognitive impairment of HIV infected adults taking ART. This study will last at least 24 weeks and has two steps. Patients will be stratified by HIV viral load and their neurocognitive state at study screening. In Step I, patients will be randomly assigned to one of two groups. Group 1 participants will receive twice-daily minocycline for 24 weeks; Group 2 participants will receive placebo. At the end of Phase I, study participants will be offered to enter Step II; all participants in Step II will receive twice-daily minocycline for an additional 24 weeks. There will be a total of 8 study visits: 5 visits for Step I (including the entry visit) and 3 visits for Step II. Medical history will occur at all visits. Blood collection will occur at all visits. Participants who have positive nonreactive rapid plasma regain (RPR) values at screening will have mandatory lumbar punctures; for those with negative serum RPR results lumbar punctures are optional. Participants who test positive for syphilis will also have a lumbar puncture at their discretion to determine if syphilis has affected the brain. A neurological exam, other neuropsychological, dementia, and depression scale assessments, and urine collection will occur at most visits. Patients will be asked to complete a questionnaire on daily living at study entry and Weeks 12 and 24. Patients who have a lumbar puncture at Week 24 will receive a phone call 2 to 5 days after the procedure to report any adverse effects. Some participants may also have an electrocardiogram (ECG) during the study. For participants not on atazanavir some procedures and sample collections are optional.

Official Title
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Phase II, Randomized, Placebo-Controlled, Double-Blind Study of Minocycline in the Treatment of HIV-Associated Cognitive Impairment

Conditions
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HIV Infections

Intervention / Treatment
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* Drug: Minocycline
* Drug: Placebo (Tetracycline)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: HIV infected Currently on a stable ART regimen for at least 16 consecutive weeks prior to study entry. Participants whose regimens have changed with respect to dose or formulation are eligible, but patients who have changed to different drugs in the same class are not eligible. Participants taking atazanavir must also be taking ritonavir or a ritonavir-boosted drug to be eligible for this study. More information on this criterion can be found in the protocol. Plan to stay on current ART regimen between study screening and Week 24 AIDS Dementia Scale (ADC) Stage greater than 0 Cognitive impairment, as evidenced by neuropsychological tests administered at screening Progressive neurocognitive decline. More information on this criterion can be found in the protocol. Estimated premorbid IQ of 70 or higher indicated by an age-corrected scaled score of 5 or higher on the vocabulary section of the Wechsler Adult Intelligence Scale Revised (WAIS-R) administered at study screening Karnofsky performance score of 60 or higher Ability to sit and stand for at least 2 hours and swallow medications with an 8-ounce glass of water Willing to use acceptable methods of contraception Willing to adhere to study schedule Exclusion Criteria: Current cancers. Patients with basal cell carcinoma, in situ carcinoma of the cervix, or Kaposi's sarcoma without evidence of visceral involvement or cancer not requiring systemic chemotherapy are not excluded. Severe premorbid psychiatric illness, including schizophrenia and major depression, which, in the opinion of the investigator, may interfere with the study Active symptomatic AIDS-defining opportunistic infection within 45 days prior to study entry Previous or current confounding neurological disorders. More information on this criterion can be found in the protocol. Central nervous system infections or cancers. More information on this criterion can be found in the protocol. Systemic lupus Thyroid disease diagnosed within 24 weeks of study entry Active drug or alcohol abuse that, in the opinion of the investigator, may interfere with the study Serious illness requiring systemic treatment or hospitalization. Patients who complete therapy or are clinically stable on therapy are not excluded. Investigational agents within 45 days prior to study entry. Patients taking expanded access drugs or drugs used in an ACTG protocol for HIV treatment or for HIV-associated complications that are not prohibited by this protocol are not excluded. History of allergy/sensitivity to minocycline or other tetracyclines and their formulations Any esophageal or other condition that would interfere with a patient's ability to swallow study medication Participation in a previous clinical drug research trial of HIV-associated cognitive impairment. Patients who have had an objective decline in performance as defined by the protocol are not excluded. Any other clinically significant condition or laboratory abnormality that, in the opinion of the investigator, would interfere with the study Certain medications Certain abnormal laboratory values. Patients who test positive on nonreactive rapid plasma reagin tests (RPR)are not excluded. Inability to undergo lumbar punctures Breastfeeding

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: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm 1: Minocycline<br>100 mg orally every 12 hours | Drug: Minocycline<br>* Tetracycline antibiotic, 100 mg taken orally every 12 hours<br>|
| Placebo Comparator: Arm 2: Matching placebo<br>orally every 12 hours | Drug: Placebo (Tetracycline)<br>* Tetracycline antibiotic placebo, orally every 12 hours<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Cognitive Performance Compared to Baseline | Th cognitive performance is measured by NPZ-8. NPZ-8 is defined as the average of age and education adjusted z-scores of eight neuropsychological tests subcomponents in the neuropsychological test battery. These eight tests are: Grooved Pegboard Dominant Hand (GPD) Grooved Pegboard Non-dominant hand (GPN) Choice Reaction Time (CRT) Sequential Reaction Time (QRT) Timed Gait (TIG) Trail Making Part A (TMA) Trail Making Part B (TMB) Symbol Digit (SYD) The primary outcome is NPZ-8 score at week24 - NPZ-8 score at baseline. | At baseline and week 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Global Deficit Z-Score (GDS) | GDS on the test battery is the simple average of all 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. The outcome is the 24 week change of GDS Z-score (24 week-baseline). | At baseline and week 24 | 
| Change in Investigator's Clinical Global Impression Score (ICGIS) | Clinicians were asked to rate their overall impression about the clinical improvement or worsening of his/her study participants. They can choose from the following 7 levels: (0) No Change, (1) Mild Improvement, (2) Moderate Improvement, (3) Marked Improvement, (4) Mild Worsening, (5) Moderate Worsening, and (6) Marked Worsening. For the analysis, we simplified the outcome into the following 3 levels: (0) worsened, (1) No Change, and (2) Improved. | At week 24 | 
| Change in Cognitive Gross Motor Function Domain Z-Score | The cognitive gross motor function is a age and education adjusted z score of Timed Gait (TIG). The outcome is the 24 week change of cognitive gross motor function domain z-scores (week 24-baseline). | At baseline and week 24 | 
| Change in Fine Motor Function Domain Z-Score | The fine motor function domain score is an average of age, sex, education, and African-American ethnicity adjusted z scores of Grooved Pegboard Dominant Hand (GPD) and Grooved Pegboard Non-dominant hand (GPN). The outcome is a 24 week change of the fine motor function domain z-score (week 24-baseline). | At baseline and week 24 | 
| Change in Psychomotor Function Domain Z-Score | The psychomotor function domain score us the average of age, sex, education, and African-American ethnicity adjusted z scores of Trail Making Part A (TMA) and Trail Making Part B (TMB). The outcome is the 24 week change of psychomotor function domain z-scores (week24-baseline). | At baseline and week 24 | 
| Change in Fine Motor/Nonverbal Function Domain Z-Score | The fine motor/nonverbal function domain score is a age and education adjusted z score of Symbol Digit Test (SYD) The outcome is the 24 change of fine motor/nonverbal function domain z-score (week 24-baseline). | At baseline and week 24 | 
| Change in Information Processing Function Domain Z-Score | The information processing function domain score is the average of age and education adjusted z scores of simple and sequential reaction time - CalCAP. The outcome is the 24 week change of information processing function domain z-scores (week 24-baseline). | At baseline and week 24 | 
| Change in Verbal Memory Domain Z-Score | The verbal memory domain score is the average of age and education adjusted z scores of Hopkins Verbal Learning Test- Revised, Learning and Delayed Recall. The outcome is the 24 week change of verbal memory domain z-scores (week 24-baseline). | At baseline and week 24 | 
| Change in Frontal Systems Function Domain Z-Score | The frontal systems function domain score is the average of age and education adjusted z scores of Stroop Color Interference Test (CTP) and interference task (STP). The outcome is the 24 week change of frontal systems function domain z-score (week 24-baseline). | At baseline and week 24 | 
| Change in Karnofsky Performance Score | The original Karnofsky performance score is 11 level score which ranges between 0 to 100. The score 100 means normal and 0 means death; therefore, higher score means higher ability to perform daily tasks. For the analysis, a new dichotomous variable (no change/worse vs. better at 24 weeks compared to baseline) was created. | At baseline and week 24 | 
| Changes in Cluster of Differentiation 4 (CD4) Cell Counts (24 Weeks) | The outcome was the 24 week change in CD4 cell count (week 24-baseline). | At baseline and weeks 24 | 
| Changes in Cluster of Differentiation 8 (CD8) Cell Counts (24 Weeks) | The outcome was the 24 week change of CD8 cell counts (week 24-baseline). | At baseline and week 24 | 
| Number of Participants With Grade 2 or Higher Toxicity and/or Signs and Symptoms | Grade or higher means that adverse events were moderate, severe, or life-threatening, or death. Grade 2 or higher adverse events are lised in the Adverse Event section. | Throughout study up to week 48 | 
| Change of HIV Plasma RiboNucleic Acid (RNA) Viral Load | The original scale of HIV RNA viral load is between 30 copies/mL to infinitive. The minimum score of 30 is the lowest detectable value. The summary table categorized this continuous value to a dichotomous variable (<30 copies/mL and >= 30 copies/mL). | At baseline and week 24 | 
| Changes in Instrumental Activities of Daily Living Questionnaire | The Instrumental Activities of Daily Living (IADL) questionnaire is designed to learn more about how subjects are able to perform common tasks. There are 16 common tasks. 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, the indicator is 0. The overall IADL score is a sum of 16 indicators divided by 16; therefore, the range is between 0 and 1 and the lower score is better. The 24-week change of IADL score was changed into a categorical variable (no change/worse vs. better) at week 24 compare to baseline. | At baseline and week 24 | 
| Changes in Medication Management Test (Modified) | 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. The score ranges between 0 and 16, and higher score indicates better medication management. | At baseline and weeks 24 | 
| Changes in Protein Markers of Oxidative Stress (Unit = Counts Per Second Only) | Protein marker of oxidative stress (Ceramides, Monohexosylceramides, Dihydro Glycosyl Galceramides, and Dihexosylceramides). For all markers, the outcome is the 24 week change (week 24-baseline). | At pre-entry and Week 24 | 
| Changes in Markers of Oxidative Stress and Immune Activation (Unit=pg/mL Only) | Protein markers of oxidative stress (Protein carbonyls) and markers of immune activation (TNF-a, IL-6,CXCL8, Hepatocyte growth factor, Osteopontin, sFAS, sFAS ligand, and CXCL12). For all markers, the outcome is the 24 week change (week 24-baseline). | At pre-entry and Week 24 | 
| Changes in Markers of Oxidative Stress (Unit = Pixels/mm2 Only) | Protein marker of oxidative stress (Neurofilament heavy polypeptide). The outcome is the 24 week change (week 24-baseline). | At pre-entry and Week 24 | 
| Changes in Neurotransmitter Levels (Unit = uM Only) | Neurotransmitter levels (Glutamate, Tryptophan, Anthranilic Acid, Quinolinic Acid, Kynurenin, and 3-Hydroxykynurenine). The outcome is the 24 week change (week 24-baseline). | At pre-entry and Week 24 | 
| Changes in Alternate Psychomotor Function Z-Score | The alternate psychomotor function is defined as the mean of age, sex, education, and African-American ethnicity adjusted z scores of Trail Making Part A (TMA), and age and education adjusted z score of Symbol Digit (SYD). The outcome is the 24 week change in alternate psychomotor function z-score (week 24-baseline). | At baseline and week 24 | 
| Changes in Alternate Verbal Memory Z-Score | The alternate verbal memory was defined as a mean of age and education adjusted z score of trials 1 to 3 and delayed recall tests. The outcome is the 24 week change in alternate verbal memory z-score (week 24-baseline). | At baseline and week 24 | 
| Changes in Alternate Frontal Systems Z-Score | The alternate frontal systems was defined as a mean of age and education adjusted z score of Interference task, and age, sex, education, and African-American ethnicity adjusted z score of Trail Making Part B. The outcome was the 24 week change in alternate frontal systems z-score (week 24-baseline). | At baseline and week 24 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Treatment Experienced