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

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.

Study Type: Interventional

Study Design: Treatment, Randomized, Double Blind (Subject, Caregiver), Placebo Control, Parallel Assignment, Safety/Efficacy Study

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.

Intervention(s) in this Clinical Trial

• Drug: Minocycline
  • Tetracycline antibiotic
• Drug: Minocycline placebo
  • Tetracycline antibiotic placebo

Arms, Groups and Cohorts in this Clinical Trial

• Experimental: 1
  • 100 mg orally every 12 hours
• Placebo Comparator: 2
  • 100 mg orally every 12 hours

Primary Measures

• Change in cognitive performance compared to baseline
  • Time Frame: At Week 24
    Safety Issue?: No

Secondary Measures

• Change in Global Deficit Score (summary measure of neuropsychological test defects)
  • Time Frame: At Week 24
    Safety Issue?: No
• Change in clinical global impression by the investigator
  • Time Frame: At Week 24
    Safety Issue?: No
• Change in cognitive domain scores
  • Time Frame: At Week 24
    Safety Issue?: No
• Change in Karnofsky performance score
  • Time Frame: At Week 24
    Safety Issue?: No
• Toxicity and/or signs and symptoms of Grade 2 or higher
  • Time Frame: Throughout study
    Safety Issue?: Yes
• Development of a Grade 2 or higher toxicity and/or signs and symptoms
  • Time Frame: Throughout study
    Safety Issue?: Yes
• Changes in CD4/CD8 cell counts
  • Time Frame: At Weeks 24 and 48
    Safety Issue?: No
• HIV control status
  • Time Frame: At Weeks 24 and 48
    Safety Issue?: No
• Changes in Instrumental Activities of Daily Living Questionnaire
  • Time Frame: At Weeks 24 and 48
    Safety Issue?: No
• Changes in Medication Management Test (Modified)
  • Time Frame: At Weeks 24 and 48
    Safety Issue?: No
• Markers including, but not limited to, those of immune activation and oxidative stress/apoptosis
  • Time Frame: At pre-entry and Week 24
    Safety Issue?: No
• Changes in "alternate psychomotor function" (mean of standardized Trail Making Part A and Symbol Digit tests)
  • Time Frame: Throughout study
    Safety Issue?: No
• Changes in "alternate verbal memory" (mean of standardized trials 1 to 3 and delayed recall tests)
  • Time Frame: Throughout study
    Safety Issue?: No
• Changes in "alternate frontal systems" (mean of standardized Interference task and Trail Making Part B)
  • Time Frame: Throughout study
    Safety Issue?: No

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

Gender Eligibility for this Clinical Trial: Both

Minimum Age for this Clinical Trial: 18 Years

Maximum Age for this Clinical Trial: 65 Years

Are Healthy Volunteers Accepted for this Clinical Trial?: No

Lead Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)

Overall Clinical Trial Officials and Contacts

Ned Sacktor, MD Study Chair Department of Neurology, Johns Hopkins Bayview Medical Center  

Information obtained from ClinicalTrials.gov on July 02, 2009

Link to the current ClinicalTrials.gov record. http://clinicaltrials.gov/show/NCT00361257

Study ID Number: ACTG A5235

ClinicalTrials.gov Identifier: NCT00361257

Health Authority: United States: Food and Drug Administration

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