Effect of Deutetrabenazine on Chorea Among Patients With Huntington Disease A Randomized Clinical Trial

Importance Deutetrabenazine is a novel molecule containing deuterium, which attenuates CYP2D6 metabolism and increases active metabolite half-lives and may therefore lead to stable systemic exposure while preserving key pharmacological activity. Objective To evaluate efficacy and safety of deutetrabenazine treatment to control chorea associated with Huntington disease. Design, Setting, and Participants Ninety ambulatory adults diagnosed with manifest Huntington disease and a baseline total maximal chorea score of 8 or higher (range, 0-28; lower score indicates less chorea) were enrolled from August 2013 to August 2014 and randomized to receive deutetrabenazine (n = 45) or placebo (n = 45) in a double-blind fashion at 34 Huntington Study Group sites. Interventions Deutetrabenazine or placebo was titrated to optimal dose level over 8 weeks and maintained for 4 weeks, followed by a 1-week washout. Main Outcomes and Measures Primary end point was the total maximal chorea score change from baseline (the average of values from the screening and day-0 visits) to maintenance therapy (the average of values from the week 9 and 12 visits) obtained by in-person visits. This study was designed to detect a 2.7-unit treatment difference in scores. The secondary end points, assessed hierarchically, were the proportion of patients who achieved treatment success on the Patient Global Impression of Change (PGIC) and on the Clinical Global Impression of Change (CGIC), the change in 36-Item Short Form– physical functioning subscale score (SF-36), and the change in the Berg Balance Test. Results Ninety patients with Huntington disease (mean age, 53.7 years; 40 women [44.4%]) were enrolled. In the deutetrabenazine group, the mean total maximal chorea scores improved from 12.1 (95% CI, 11.2-12.9) to 7.7 (95% CI, 6.5-8.9), whereas in the placebo group, scores improved from 13.2 (95% CI, 12.2-14.3) to 11.3 (95% CI, 10.0-12.5); the mean between-group difference was –2.5 units (95% CI, –3.7 to –1.3) (P < .001). Treatment success, as measured by the PGIC, occurred in 23 patients (51%) in the deutetrabenazine group vs 9 (20%) in the placebo group (P = .002). As measured by the CGIC, treatment success occurred in 19 patients (42%) in the deutetrabenazine group vs 6 (13%) in the placebo group (P = .002). In the deutetrabenazine group, the mean SF-36 physical functioning subscale scores decreased from 47.5 (95% CI, 44.3-50.8) to 47.4 (44.3-50.5), whereas in the placebo group, scores decreased from 43.2 (95% CI, 40.2-46.3) to 39.9 (95% CI, 36.2-43.6), for a treatment benefit of 4.3 (95% CI, 0.4 to 8.3) (P = .03). There was no difference between groups (mean difference of 1.0 unit; 95% CI, –0.3 to 2.3; P = .14), for improvement in the Berg Balance Test, which improved by 2.2 units (95% CI, 1.3-3.1) in the deutetrabenazine group and by 1.3 units (95% CI, 0.4-2.2) in the placebo group. Adverse event rates were similar for deutetrabenazine and placebo, including depression, anxiety, and akathisia. Conclusions and Relevance Among patients with chorea associated with Huntington disease, the use of deutetrabenazine compared with placebo resulted in improved motor signs at 12 weeks. Further research is needed to assess the clinical importance of the effect size and to determine longer-term efficacy and safety

A randomized, double-blind, placebo-controlled trial of deprenyl and thioctic acid in human immunodeficiency virus-associated cognitive impairment

Cognitive impairment is a frequent manifestation of advanced human immunodeficiency virus (HIV) infection. The response to antiretroviral medication is often partial and poorly sustained. Recent studies suggest that free radical production within the CNS and neuronal apoptosis may play important roles in the pathogenesis of HIV dementia. We conducted a randomized double-blind, placebo-controlled trial using a parallel group, 2× 2 factorial design evaluating deprenyl, a monoamine oxidase B inhibitor and putative anti-apoptotic agent, and thioctic acid, an antioxidant, in 36 patients with HIV-associated cognitive impairment. Both deprenyl and thioctic acid were well tolerated with few adverse events. Deprenyl recipients showed significant improvement on tests of verbal memory compared with patients not taking deprenyl. Thioctic acid treatment did not improve cognitive function. These results suggest that deprenyl treatment is associated with cognitive improvement in subjects with mild HIV-associated cognitive impairment, whereas thioctic acid has no benefit. A larger efficacy trial is needed to assess the long-term effect of deprenyl on cognitive performance in patients with HIV infection. Human immunodeficiency virus type 1 (HIV-1)-associated dementia complex(HIV dementia) occurs in 15 to 20% of acquired immunodeficiency syndrome(AIDS) patients and is characterized by cognitive impairment, motor dysfunction, and behavioral changes.1-5 The cognitive impairment includes mental slowing, forgetfulness, and poor concentration. Motor symptoms include loss of fine motor control, clumsiness, unsteady gait, and tremor. Behavioral changes include apathy, lethargy, and depression.2,3,6 HIV dementia is usually a rapidly progressive disorder with a mean survival of about 6 months,2 although recently, patients with slower progression or a stable course have been identified.7 HIV-1-associated minor cognitive motor disorder, a milder syndrome, is estimated to occur in 25% of patients with symptomatic HIV infection.8 Few available antiretroviral agents have been studied for the treatment of HIV dementia. Open label studies with zidovudine (ZDV) in demented patients showed improvements in clinical functioning, neuropsychological performance, and neuroimaging studies.9 ZDV, in a placebo-controlled blinded study, also improved neuropsychological function in AIDS or AIDS-related complex patients without dementia.10 The only placebo-controlled trial of ZDV in HIV dementia demonstrated the greatest neurocognitive improvement only with very high dosages (i.e., 2,000 mg/day).11 Unfortunately, the response to ZDV treatment may be short-lived or associated with intolerable side effects and therefore often unsatisfactory. There is very limited information about the therapeutic effects of other antiretroviral medications (e.g., dideoxynucleosides)12 or protease inhibitors. Neurotoxins from HIV-infected activated macrophages or microglia interacting with astrocytes may play a central pathogenetic role in HIV dementia.13,14 Putative neurotoxins include cytokines (tumor necrosis factor alpha [TNF-α]) and oxygen radicals.2,15 Both TNF-α and hydroxyl free radicals may stimulate apoptosis (programmed cell death), and apoptotic neurons have been demonstrated in the cerebral cortex and basal ganglia of both children and adults with HIV encephalitis.16,17 We hypothesized that these indirect mechanisms of neuronal injury could be modified by deprenyl and thioctic acid to improve or even prevent HIV-associated cognitive impairment. Deprenyl, a selective monoamine oxidase type B inhibitor, at very low dosages in in vitro and in vivo systems has a trophic effect on injured neurons.18-21 Thioctic acid is a naturally occurring enzymatic cofactor for pyruvate dehydrogenase and alpha oxoglutarate dehydrogenase and scavenges harmful hydroxyl radicals and other reactive oxygen species.22,23 We conducted a randomized, double-blind, placebo-controlled clinical trial of deprenyl and thioctic acid to assess their safety and tolerability and to assess their impact on HIV-associated cognitive impairment in HIV seropositive (HIV+) patients

Medication Management Skill in HIV: I. Evidence for Adaptation of Medication Management Strategies in People with Cognitive Impairment. II. Evidence for a Pervasive Lay Model of Medication Efficacy

Objective: We investigated sex differences in verbal memory across different levels of neural dysfunction, measured by temporal lobe glucose metabolic rates (TLGluMR). Methods: Three hundred ninety controls and 672 participants with amnestic mild cognitive impairment (aMCI) and 254 with Alzheimer disease (AD) dementia from the Alzheimer's Disease Neuroimaging Initiative completed the Rey Auditory Verbal Learning Test (RAVLT) and [18F]-fluorodeoxyglucose–PET. Cross-sectional analyses were conducted using linear regression to examine the sex by TLGluMR interaction on RAVLT performance in the overall sample and within diagnostic groups adjusting for age, education, and APOE ε4 genotype. Results: Across groups, female sex and higher TLGluMR and their interaction were associated with better verbal memory (p values ≤ 0.005). The female advantage in verbal memory varied by TLGluMR such that the advantage was greatest among individuals with moderate to high TLGluMR and minimal or absent among individuals with lower TLGluMR. Diagnosis-stratified analyses revealed that this interaction was driven by the aMCI group (p values = 0.009). The interaction was not significant in control and AD dementia groups. Conclusions: Women show better verbal memory than men in aMCI despite similar levels of brain hypometabolism. The lifelong advantage that females show over males in verbal memory might represent a form of cognitive reserve that delays verbal memory decline until more advanced pathology, as indexed by TLGluMR. This issue is clinically important because verbal memory scores are used in diagnosing aMCI and AD dementia

Effect of Deutetrabenazine on Chorea Among Patients With Huntington Disease: A Randomized Clinical Trial

IMPORTANCE: Deutetrabenazine is a novel molecule containing deuterium, which attenuates CYP2D6 metabolism and increases active metabolite half-lives and may therefore lead to stable systemic exposure while preserving key pharmacological activity. OBJECTIVE: To evaluate efficacy and safety of deutetrabenazine treatment to control chorea associated with Huntington disease. DESIGN, SETTING, AND PARTICIPANTS: Ninety ambulatory adults diagnosed with manifest Huntington disease and a baseline total maximal chorea score of 8 or higher (range, 0-28; lower score indicates less chorea) were enrolled from August 2013 to August 2014 and randomized to receive deutetrabenazine (n = 45) or placebo (n = 45) in a double-blind fashion at 34 Huntington Study Group sites. INTERVENTIONS: Deutetrabenazine or placebo was titrated to optimal dose level over 8 weeks and maintained for 4 weeks, followed by a 1-week washout. MAIN OUTCOMES AND MEASURES: Primary end point was the total maximal chorea score change from baseline (the average of values from the screening and day-0 visits) to maintenance therapy (the average of values from the week 9 and 12 visits) obtained by in-person visits. This study was designed to detect a 2.7-unit treatment difference in scores. The secondary end points, assessed hierarchically, were the proportion of patients who achieved treatment success on the Patient Global Impression of Change (PGIC) and on the Clinical Global Impression of Change (CGIC), the change in 36-Item Short Form- physical functioning subscale score (SF-36), and the change in the Berg Balance Test. RESULTS: Ninety patients with Huntington disease (mean age, 53.7 years; 40 women [44.4%]) were enrolled. In the deutetrabenazine group, the mean total maximal chorea scores improved from 12.1 (95% CI, 11.2-12.9) to 7.7 (95% CI, 6.5-8.9), whereas in the placebo group, scores improved from 13.2 (95% CI, 12.2-14.3) to 11.3 (95% CI, 10.0-12.5); the mean between-group difference was -2.5 units (95% CI, -3.7 to -1.3) (P \u3c .001). Treatment success, as measured by the PGIC, occurred in 23 patients (51%) in the deutetrabenazine group vs 9 (20%) in the placebo group (P = .002). As measured by the CGIC, treatment success occurred in 19 patients (42%) in the deutetrabenazine group vs 6 (13%) in the placebo group (P = .002). In the deutetrabenazine group, the mean SF-36 physical functioning subscale scores decreased from 47.5 (95% CI, 44.3-50.8) to 47.4 (44.3-50.5), whereas in the placebo group, scores decreased from 43.2 (95% CI, 40.2-46.3) to 39.9 (95% CI, 36.2-43.6), for a treatment benefit of 4.3 (95% CI, 0.4 to 8.3) (P = .03). There was no difference between groups (mean difference of 1.0 unit; 95% CI, -0.3 to 2.3; P = .14), for improvement in the Berg Balance Test, which improved by 2.2 units (95% CI, 1.3-3.1) in the deutetrabenazine group and by 1.3 units (95% CI, 0.4-2.2) in the placebo group. Adverse event rates were similar for deutetrabenazine and placebo, including depression, anxiety, and akathisia. CONCLUSIONS AND RELEVANCE: Among patients with chorea associated with Huntington disease, the use of deutetrabenazine compared with placebo resulted in improved motor signs at 12 weeks. Further research is needed to assess the clinical importance of the effect size and to determine longer-term efficacy and safety. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01795859

Clinical confirmation of the American Academy of Neurology algorithm for HIV-1-associated cognitive/motor disorder

Objective: Our goal was to put into operation the American Academy of Neurology (AAN) algorithm for the definition of minor cognitive/motor disorder and human immunodeficiency virus type 1 (HIV-1)-associated dementia complex (ADC) and examine the neuropsychological, neurologic, psychiatric, and functional deficits in affected subjects. Design: Two hundred seventy-one HIV-positive men and women with CD4 count of <200 or demonstrated cognitive impairment were recruited from three sites (Columbia University, The Johns Hopkins University, and the University of Rochester) and underwent standardized assessments. Results: Sixty-five subjects met criteria for ADC (cognitive, functional, and neurologic or behavioral), 56 met criteria for minor cognitive/motor disorder, and 150 met criteria for neither. Seventy-eight subjects met neuropsychological and neurologic/behavioral criteria but did not demonstrate functional impairment. Those with ADC performed significantly worse on speeded motor and verbal memory tests and demonstrated more extrapyramidal signs and behavioral symptoms than did the other two groups. Both ADC and minor cognitive/motor disorder were independently predictive of poor physical function, after adjustment for age, gender, years of education, log (CD4 count), hemoglobin, number of HIV diagnoses and medications, and depression. Conclusions: The operationalization of AAN criteria demonstrates that it is rare to have both cognitive and functional impairment without associated neurologic and/or behavioral deficits. Functional impairment in isolation is also rare. Dementia is an independent predictor of physical function. NEUROLOGY 1996;47: 1247-125

Safety and tolerability of the antioxidant OPC-14117 in HIV-associated cognitive impairment

Cognitive impairment is a common and disabling complication of advanced HIV infection. Antiretroviral agents are the only proven therapies currently used for the treatment of HIV dementia, but the response to these agents is frequently unsatisfactory, short-lived, or complicated by intolerable side effects. We hypothesized that OPC-14117, a lipophilic antioxidant that acts to scavenge superoxide anion radicals, might ameliorate the toxic interactions between HIV infected macrophages and neurons. We conducted a double-blind, placebo-controlled, randomized clinical trial to assess the safety and tolerability of OPC-14117 240 mg per day. All 30 patients enrolled(15 per group) had cognitive impairment based on performance on neuropsychological tests. The primary outcome was tolerability of the study drug as measured by the proportion of subjects able to complete the study on their assigned dosage of experimental medication. Overall OPC-14117 was as well tolerated as placebo. Five subjects withdrew because of adverse experiences (two placebo, three OPC-14117). The OPC-14117-treated group had better scores on a clinical global impression scale, compared with the placebo group. There were trends toward improvement in the cognitive test scores; however, these changes were not statistically significant. These results demonstrate that this antioxidant intervention is well tolerated in cognitively impaired patients with advanced HIV infection, and suggest that a larger efficacy trial to assess the impact of OPC-14117 on cognitive performance is warranted

Safety, tolerability, and efficacy of PBT2 in Huntington's disease: A phase 2, randomised, double-blind, placebo-controlled trial

Background: PBT2 is a metal protein-attenuating compound that might reduce metal-induced aggregation of mutant huntingtin and has prolonged survival in a mouse model of Huntington's disease. We aimed to assess the safety, tolerability, and efficacy of PBT2 in patients with Huntington's disease. Methods: In this 26-week, randomised, double-blind, placebo-controlled trial, adults ( ≥ 25 years old ) with early-stage to mid-stage Huntington's disease were randomly assigned ( 1:1:1 ) by a centralised interactive response system to once daily PBT2 250 mg, PBT2 100 mg, or placebo. Randomisation was stratified by site with a block size of three. Participants, carers, the steering committee, site investigators, study staff, and the study sponsor were masked to treatment assignment. Primary endpoints were safety and tolerability. The safety population consisted of all participants who were randomly assigned and had at least one dose of study drug. The principal secondary endpoint was cognition, measured by the change from baseline to week 26 in the main composite Z score of five cognitive tests ( Category Fluency Test, Trail Making Test Part B, Map Search, Symbol Digit Modalities Test, and Stroop Word Reading Test ) and scores on eight individual cognitive tests ( the five aforementioned plus the Trail Making Test Part A, Montreal Cognitive Assessment, and the Speeded Tapping Test ). The intention-to-treat population comprised participants who were randomly assigned and had at least one efficacy assessment after administration of study drug. This trial is registered with [http://clinicaltrials.gov/] ClinicalTrials.gov, [http://clinicaltrials.gov/show/NCT01590888] NCT01590888. Findings: Between April 18, 2012, and Dec 14, 2012, 109 participants were randomly assigned to PBT2 250 mg ( n=36 ), PBT2 100 mg ( n=38 ), or placebo ( n=35 ) at 19 research centres in Australia and the USA. 32 ( 89% ) individuals on PBT2 250 mg, 38 ( 100% ) on PBT2 100 mg, and 34 ( 97% ) on placebo completed the study. Six serious adverse events ( acute coronary syndrome, major depression, pneumonia, suicide attempt, viral infection, and worsening of Huntington's disease ) occurred in five participants in the PBT2 250 mg group, three ( fall with subdural haematoma, suicide attempt, and hospital admission for stabilisation of Huntington's disease ) occurred in two participants in the PBT2 100 mg group, and one ( increasing aggression ) occurred in a participant in the placebo group. The site investigators deemed all, except the worsening of Huntington's disease, as unrelated to study drug. 32 ( 89% ) participants on PBT2 250 mg, 30 ( 79% ) on PBT2 100 mg, and 28 ( 80% ) on placebo had at least one adverse event. Compared with placebo, neither PBT2 100 mg ( least-squares mean 0·02, 95% CI −0·10 to 0·14; p=0·772 ) nor PBT2 250 mg ( 0·07, −0·05 to 0·20; p=0·240 ) significantly improved the main composite cognition Zscore between baseline and 26 weeks. Compared with placebo, the Trail Making Test Part B score was improved between baseline and 26 weeks in the PBT2 250 mg group ( 17·65 s, 0·65–34·65; p=0·042 ) but not in the 100 mg group ( 0·79 s improvement, −15·75 to 17·32; p=0·925 ); neither dose significantly improved cognition on the other tests. Interpretation: PBT2 was generally safe and well tolerated in patients with Huntington's disease. The potential benefit on executive function will need to be confirmed in a larger study. Funding: Prana Biotechnology Limited