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A Phase II, Placebo-controlled, Double-blind Study of the Selegiline Transdermal System in the Treatment of HIV-associated Cognitive Impairment
Giovanni Schifitto*1, N Sacktor2, J Zhang3, S Evans3, D Simpson4, L Millar5, E Miller6, E Smith7, M Goodhead8, D Clifford9, and the ACTG A5090 Team
1Univ of Rochester Sch of Med and Dentistry, NY, US; 2Johns Hopkins Univ, Baltimore, MD, US; 3Harvard Sch of Publ Hlth, Boston, MA, US; 4Mt Sinai Sch of Med, New York, NY, US; 5Frontier Sci & Tech Res Fndn, Amherst, NY, US; 6David Geffen Sch of Med, Univ of California, Los Angeles Med Ctr, US; 7NIAID, NIH, DHHS, Bethesda, MD, US; 8Somerset Pharma, Tampa, FL, US; and 9Washington Univ, St Louis, MO, US
Background: Cognitive impairment continues to be a
significant neurological complication of HIV infection and has been associated
with oxidative stress-induced neuronal injury. Selegiline is an monoamine
oxidase-B (MAO-B) inhibitor capable of decreasing oxygen-free radicals,
increasing the formation of the antioxidant enzymes superoxide
dismutase (SOD) and catalase, and providing additional neuroprotection
by enhancing the synthesis of neurotrophic factors. The above rationale has led
to the design and implementation of ACTG 5090.
Methods: We enrolled 128 HIV-1-infected individuals
with impaired cognitive functioning in this placebo-controlled, 3-arm study of
selegiline transdermal system (STS) across 17 sites. Cognitive impairment was
determined using a standard battery of neuropsychological tests. Subjects were
required to be on stable ART regimens (or ART-free) for at least 8 weeks prior
to screening. Participants were stratified according to HIV viral load (<200
vs ≥200 copies/mL) and clinical stage of the AIDS dementia complex (ADC)
(0.5 vs ≥1), and randomized to receive STS 0.5mg x 20 cm2, STS
1.0 mg x 20 cm2, or matching placebo patches daily. The primary
efficacy endpoint was defined as the change in neuropsychological composite
Z-score (NPZ6) from baseline to week 24. Measures of safety included
frequencies of adverse experiences and abnormal results on laboratory tests.
Results: Of the 128 subjects enrolled, 88% were men and
51% were white. Median age was 45 years, CD4 = 422 cells/mm3, plasma
HIV RNA <200 copies/mL = 69%; 97% were on ART at baseline; 36% had equivocal
or subclinical ADC, and 62% mild to moderate ADC; 96 subjects completed the
24-week study treatment. The 3 arms had comparable NPZ6 scores at baseline. The
24 week NPZ6 median (interquartile range) changes were 0.22 (–0.28, 0.55) for
the selegiline 0.5-mg arm, 0.21 (–0.18, 0.62) for the selegiline 1-mg arm and
0.28 (0.16, 0.64) for the placebo arm. There was insufficient evidence to
conclude between-arm differences with respect to 24-week NPZ6 changes (p
= 0.914). Severe laboratory abnormalities were few and occurred in similar
proportion among the three treatment arms.
Conclusions: The preliminary analyses of this 24-week trial
suggest that selegiline treatment was safe but not effective at improving
cognitive function in subjects with HIV-associated cognitive impairment
relative to placebo. Additional analyses are underway to assess the effect of
selegiline on quality of life and functional performance.
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