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A randomized clinical trial of CPI-1189 for HIV-associated cognitive–motor impairment

From the Department of Neurology (Dr. Clifford), Washington University, St. Louis, MO; Department of Neurology (Dr. McArthur) Johns Hopkins University, Baltimore, MD; Department of Neurology (Drs. Schifitto, Kieburtz, and McDonald), University of Rochester, NY; Department of Neurology (Dr. Cohen), Northwestern University, Chicago, IL; Department of Neurology (Dr. Marder), Columbia University, New York, NY; Departments of Neurology (Dr. Ellis) and Medicine (Dr. Letendre), University of San Diego, CA; and Department of Neurology (Dr. Marra), University of Washington, Seattle.

Address correspondence and reprint requests to Dr. David B. Clifford, Box 8111, Department of Neurology, 660 S. Euclid Ave., St. Louis, MO 63110; e-mail: cliffordd{at}neuro.wustl.edu

Background: CPI-1189 is a compound with antioxidant properties that blocks tumor necrosis factor- (TNF) effects in animal models. It has neuroprotective properties in model systems for HIV-associated neurotoxicity and thus is a candidate for neuroprotective therapy in humans with HIV-associated CNS disease.

Objective: To assess the tolerability and safety of CPI-1189 in treating HIV-associated cognitive–motor impairment.

Methods: Sixty-four subjects with mild to moderate HIV-associated cognitive–motor impairment were randomized to receive either placebo or 50 or 100 mg daily of CPI-1189 in addition to optimal HIV therapy. Subjects were followed prospectively in a double-masked study for 10 weeks. The primary assessment was tolerability and safety of the compound. Secondary objectives examined neuropsychological and functional change associated with this treatment.

Results: The study compound was well tolerated, with 91% of CPI-1189-treated subjects and 76% of placebo-treated subjects completing the trial. Skin rash was seen equally in placebo and active arms, but the only study withdrawals due to skin rash occurred in CPI-1189-treated subjects (n = 2). One subject developed a cataract on drug (100 mg/day). CD4 lymphocyte counts and plasma HIV viral load remained stable in all groups throughout the trial. No significant treatment effects were observed on the change in composite Z-scores for eight neuropsychologic measures (NPZ-8). The Grooved Pegboard Test (nondominant) showed improved performance with CPI-1189 at 100 mg/day (p = 0.01), but no other neuropsychometric or functional measures demonstrated significant improvement.

Conclusions: CPI-1189 was well tolerated in HIV subjects with cognitive–motor disorder. This study was not powered to conclusively determine efficacy and showed no consistent treatment-associated improvement in cognitive or functional measures.

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