Clinical trial NCT00361257: Minocycline for the Treatment of Decreased Mental Function in HIV-Infected Adults
Official title: Phase II, Randomized, Placebo-Controlled, Double-Blind Study of Minocycline in the Treatment of HIV-Associated Cognitive Impairment
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: HIV Infections
Keywords: Treatment Experienced
Lead sponsor: Advancing Clinical Therapeutics Globally for HIV/AIDS and Other Infections
Sponsor class: NETWORK
Collaborators: name: National Institute of Allergy and Infectious Diseases (NIAID)
name: Neurologic AIDS Research Consortium (NARC)
First posted: 2006-08-08
Enrollment: 107
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: 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

Primary outcomes:
measure: Change in Cognitive Performance Compared to Baseline
timeFrame: At baseline and week 24
Secondary outcomes:
measure: Change in Global Deficit Z-Score (GDS)
timeFrame: At baseline and week 24
measure: Change in Investigator's Clinical Global Impression Score (ICGIS)
timeFrame: At week 24
measure: Change in Cognitive Gross Motor Function Domain Z-Score
timeFrame: At baseline and week 24
measure: Change in Fine Motor Function Domain Z-Score
timeFrame: At baseline and week 24
measure: Change in Psychomotor Function Domain Z-Score
timeFrame: At baseline and week 24
measure: Change in Fine Motor/Nonverbal Function Domain Z-Score
timeFrame: At baseline and week 24
measure: Change in Information Processing Function Domain Z-Score
timeFrame: At baseline and week 24
measure: Change in Verbal Memory Domain Z-Score
timeFrame: At baseline and week 24
measure: Change in Frontal Systems Function Domain Z-Score
timeFrame: At baseline and week 24
measure: Change in Karnofsky Performance Score
timeFrame: At baseline and week 24
measure: Changes in Cluster of Differentiation 4 (CD4) Cell Counts (24 Weeks)
timeFrame: At baseline and weeks 24
measure: Changes in Cluster of Differentiation 8 (CD8) Cell Counts (24 Weeks)
timeFrame: At baseline and week 24
measure: Number of Participants With Grade 2 or Higher Toxicity and/or Signs and Symptoms
timeFrame: Throughout study up to week 48
measure: Change of HIV Plasma RiboNucleic Acid (RNA) Viral Load
timeFrame: At baseline and week 24
measure: Changes in Instrumental Activities of Daily Living Questionnaire
timeFrame: At baseline and week 24
measure: Changes in Medication Management Test (Modified)
timeFrame: At baseline and weeks 24
measure: Changes in Protein Markers of Oxidative Stress (Unit = Counts Per Second Only)
timeFrame: At pre-entry and Week 24
measure: Changes in Markers of Oxidative Stress and Immune Activation (Unit=pg/mL Only)
timeFrame: At pre-entry and Week 24
measure: Changes in Markers of Oxidative Stress (Unit = Pixels/mm2 Only)
timeFrame: At pre-entry and Week 24
measure: Changes in Neurotransmitter Levels (Unit = uM Only)
timeFrame: At pre-entry and Week 24
measure: Changes in Alternate Psychomotor Function Z-Score
timeFrame: At baseline and week 24
measure: Changes in Alternate Verbal Memory Z-Score
timeFrame: At baseline and week 24
measure: Changes in Alternate Frontal Systems Z-Score
timeFrame: At baseline and week 24
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: UCLA-David Geffen School of Medicine
state: California
city: San Diego
country: United States
facility: University of California
state: California
city: Denver
country: United States
facility: University of Colorado Health Science Center
state: Colorado
city: Atlanta
country: United States
facility: The Ponce de Leon Ctr. CRS
state: Georgia
city: Chicago
country: United States
facility: Northwestern University CRS
state: Illinois
city: Baltimore
country: United States
facility: Johns Hopkins School of Medicine
state: Maryland
city: Boston
country: United States
facility: Massachusetts General Hospital, Division of Infectious Diseases
state: Massachusetts
city: Detroit
country: United States
facility: Henry Ford Hosp. CRS
state: Michigan
city: St. Louis
country: United States
facility: Washington University
state: Missouri
city: New York
country: United States
facility: NYU Med Ctr, Dept of Medicine
state: New York
city: Rochester
country: United States
facility: 1101 University of Rochester Medical Center, Division of Infectious Diseases
state: New York
city: Chapel Hill
country: United States
facility: University of North Carolina, AIDS Clinical Trials Unit
state: North Carolina
city: Portland
country: United States
facility: The Research and Education Group - Portland CRS
state: Oregon
city: Philadelphia
country: United States
facility: University of Pennsylvania, ACTU
state: Pennsylvania
city: Richmond
country: United States
facility: Virginia Commonwealth Univ. Medical Ctr. CRS
state: Virginia
city: Seattle
country: United States
facility: Univ of Washington, Harborview Medical Ctr
state: Washington
Study officials:
affiliation: Department of Neurology, Johns Hopkins Bayview Medical Center
name: Ned Sacktor, MD
role: STUDY_CHAIR
References:
citation: Bell JE. An update on the neuropathology of HIV in the HAART era. Histopathology. 2004 Dec;45(6):549-59. doi: 10.1111/j.1365-2559.2004.02004.x.
citation: Ferrari S, Vento S, Monaco S, Cavallaro T, Cainelli F, Rizzuto N, Temesgen Z. Human immunodeficiency virus-associated peripheral neuropathies. Mayo Clin Proc. 2006 Feb;81(2):213-9. doi: 10.4065/81.2.213.
citation: Zink MC, Uhrlaub J, DeWitt J, Voelker T, Bullock B, Mankowski J, Tarwater P, Clements J, Barber S. Neuroprotective and anti-human immunodeficiency virus activity of minocycline. JAMA. 2005 Apr 27;293(16):2003-11. doi: 10.1001/jama.293.16.2003.
citation: Sacktor N, Miyahara S, Deng L, Evans S, Schifitto G, Cohen BA, Paul R, Robertson K, Jarocki B, Scarsi K, Coombs RW, Zink MC, Nath A, Smith E, Ellis RJ, Singer E, Weihe J, McCarthy S, Hosey L, Clifford DB; ACTG A5235 team. Minocycline treatment for HIV-associated cognitive impairment: results from a randomized trial. Neurology. 2011 Sep 20;77(12):1135-42. doi: 10.1212/WNL.0b013e31822f0412. Epub 2011 Sep 7.
citation: Sacktor N, Miyahara S, Evans S, Schifitto G, Cohen B, Haughey N, Drewes JL, Graham D, Zink MC, Anderson C, Nath A, Pardo CA, McCarthy S, Hosey L, Clifford D; ACTG A5235 team. Impact of minocycline on cerebrospinal fluid markers of oxidative stress, neuronal injury, and inflammation in HIV-seropositive individuals with cognitive impairment. J Neurovirol. 2014 Dec;20(6):620-6. doi: 10.1007/s13365-014-0292-0. Epub 2014 Nov 7.