Charles S. Venuto

Inosine to increase serum and cerebrospinal fluid urate in Parkinson disease: a randomized clinical trial.

IMPORTANCE Convergent biological, epidemiological, and clinical data identified urate elevation as a candidate strategy for slowing disability progression in Parkinson disease (PD). OBJECTIVE To determine the safety, tolerability, and urate-elevating capability of the urate precursor inosine in early PD and to assess its suitability and potential design features for a disease-modification trial. DESIGN, SETTING, AND PARTICIPANTS The Safety of Urate Elevation in PD (SURE-PD) study, a randomized, double-blind, placebo-controlled, dose-ranging trial of inosine, enrolled participants from 2009 to 2011 and followed them for up to 25 months at outpatient visits to 17 credentialed clinical study sites of the Parkinson Study Group across the United States. Seventy-five consenting adults (mean age, 62 years; 55% women) with early PD not yet requiring symptomatic treatment and a serum urate concentration less than 6 mg/dL (the approximate population median) were enrolled. INTERVENTIONS Participants were randomized to 1 of 3 treatment arms: placebo or inosine titrated to produce mild (6.1-7.0 mg/dL) or moderate (7.1-8.0 mg/dL) serum urate elevation using 500-mg capsules taken orally up to 2 capsules 3 times per day. They were followed for up to 24 months (median, 18 months) while receiving the study drug plus 1 washout month. MAIN OUTCOMES AND MEASURES The prespecified primary outcomes were absence of unacceptable serious adverse events (safety), continued treatment without adverse event requiring dose reduction (tolerability), and elevation of urate assessed serially in serum and once (at 3 months) in cerebrospinal fluid. RESULTS Serious adverse events (17), including infrequent cardiovascular events, occurred at the same or lower rates in the inosine groups relative to placebo. No participant developed gout and 3 receiving inosine developed symptomatic urolithiasis. Treatment was tolerated by 95% of participants at 6 months, and no participant withdrew because of an adverse event. Serum urate rose by 2.3 and 3.0 mg/dL in the 2 inosine groups (P < .001 for each) vs placebo, and cerebrospinal fluid urate level was greater in both inosine groups (P = .006 and <.001, respectively). Secondary analyses demonstrated nonfutility of inosine treatment for slowing disability. CONCLUSIONS AND RELEVANCE Inosine was generally safe, tolerable, and effective in raising serum and cerebrospinal fluid urate levels in early PD. The findings support advancing to more definitive development of inosine as a potential disease-modifying therapy for PD. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00833690.

Pharmacologic approaches to the treatment of Huntington's disease

Huntingtons disease (HD) is an inherited, progressive neurodegenerative disorder characterized by chorea, cognitive impairment, and behavioral disturbances. Despite advances in diagnosis and improved understanding of HD, treatment remains difficult due to challenging symptoms and a paucity of approved therapeutic interventions. Nonpharmacologic and pharmacologic strategies have been evaluated; regarding the latter, over 80 agents of various classes have been investigated in clinical trials or examined in case reports. Symptomatic treatment, however, is generally confined to antidopaminergic agents for motor dysfunction and antidepressants for mood disorders, while treatment for cognitive dysfunction remains vacant. Several different mechanisms to modify symptoms and disease progression have been targeted in clinical trials. This article reviews some of the more common pharmacologic treatments used for HD, discusses data regarding suboptimal agents that have been tested, and surveys treatments under investigation.

Novel Methods and Technologies for 21st-Century Clinical Trials: A Review

IMPORTANCE New technologies are rapidly reshaping health care. However, their effect on drug development to date generally has been limited. OBJECTIVES To evaluate disease modeling and simulation, alternative study design, novel objective measures, virtual research visits, and enhanced participant engagement and to examine their potential effects as methods and tools on clinical trials. EVIDENCE REVIEW We conducted a systematic search of relevant terms on PubMed (disease modeling and clinical trials; adaptive design, clinical trials, and neurology; Internet, clinical trials, and neurology; and telemedicine, clinical trials, and neurology), references of previous publications, and our files. The search encompassed articles published from January 1, 2000, through November 30, 2014, and produced 7976 articles, of which 22 were determined to be relevant and are included in this review. FINDINGS Few of these new methods and technologies have been applied to neurology clinical trials. Clinical outcomes, including cognitive and stroke outcomes, increasingly are captured remotely. Other therapeutic areas have successfully implemented many of these tools and technologies, including web-enabled clinical trials. CONCLUSIONS AND RELEVANCE Increased use of new tools and approaches in future clinical trials can enhance the design, improve the assessment, and engage participants in the evaluation of novel therapies for neurologic disorders.

Multidrug resistance 1 polymorphisms and trough concentrations of atazanavir and lopinavir in patients with HIV

INTRODUCTION HIV-infected patients receiving protease inhibitors may benefit from therapeutic drug monitoring-assisted dose adjustment to achieve target plasma concentrations. However, efflux pumps such as permeability-glycoprotein, which is encoded by the multidrug resistance (MDR)1 gene, may decrease intracellular drug concentrations, thus reducing the amount of drug at the site of action. Plasma concentrations of protease inhibitors and CD4 cell count response have been associated with the T allele at the MDR1 C3435T locus. We examined MDR1 single nucleotide polymorphisms in a cohort of patients in whom therapeutic drug monitoring is ongoing through a research protocol. METHODS In a multicenter study, genotypic analyses at two MDR1 loci, C3435T and G2677T, were performed by a real-time polymerase chain reaction method using DNA from 103 patients categorized as substance users or nonusers on atazanavir or lopinavir as the primary antiretrovirals. Allelic frequencies were determined as a function of racial/ethnic background, substance use status and trough concentrations of atazanavir and lopinavir. RESULTS The C/T and G/T alleles at the MDR1 C3435T and G2677T loci were equally frequent in the Caucasian population, but the wild-type alleles were more prevalent in the African-American population (59% homozygous [CC] and 32% heterozygous [CT] for C3435T; 80% homozygous [GG] and 16% heterozygous [GT] for G2677T). The frequencies in the Hispanic population were 46% CC and 38% CT for C3435T, and 58% GG and 38% GT for G2677T. No significant differences were seen in allele frequencies for MDR1 polymorphisms in substance user versus nonuser groups. Trough plasma concentrations of atazanavir or lopinavir were not correlated with the variant T allele. CONCLUSIONS These data confirm the higher prevalence of wild-type alleles of the MDR1 gene in African-Americans and the linkage disequilibrium between C3435T and G2677T loci. The T allele at the MDR1 C3435T and G2677T loci was not associated with higher atazanavir or lopinavir trough concentrations.

Alternative Therapies for Clostridium difficile Infections

Clostridium difficile infection is a serious condition responsible for significant morbidity and mortality, especially in patients being treated with antimicrobials. Increasing frequency of the infection and hypervirulent C. difficile strains have resulted in more severe disease as well as therapeutic failures with traditional treatment (metronidazole and vancomycin). To review the studies assessing nontraditional therapies for the prevention and treatment of primary or recurrent C. difficile infection, we conducted a literature search of the PubMed‐MEDLINE databases (1984–2010). Of the 98 studies identified, 21 met our inclusion criteria. Five clinical trials and one retrospective medical record review evaluated probiotic or prebiotic formulations for the prevention of C. difficile infection. Only one of these studies, which included Lactobacillus casei and L. bulgaricus in the probiotic formulation, showed efficacy. Ten clinical trials evaluated treatment of an initial episode of C. difficile infection (primary treatment) with the antimicrobials fidaxomicin, fusidic acid, rifampin, teicoplanin, and nitazoxanide, as well as the toxin‐binding polymer, tolevamer. Only nitazoxanide and teicoplanin demonstrated noninferiority when compared with vancomycin or metronidazole. Four prospective studies and one retrospective study evaluated treatment of relapsing C. difficile infection. Prebiotic formulations for the prevention and treatment of recurrent C. difficile infection have not proved to be clinically warranted. Nitazoxanide, teicoplanin, and fidaxomicin may be considered as alternatives to traditional treatment; however, clinical experience is limited with these agents for this indication. Bacteriotherapy with fecal instillation has demonstrated high clinical cure rates in case studies and in a retrospective study; however, to our knowledge, randomized clinical trials are lacking for this therapeutic approach. As C. difficile infection rates continue to increase and hypervirulent strains continue to emerge, it is important for future clinical studies to assess alternative therapies.

Oral Ketamine for Children with Chronic Pain: A Pilot Phase 1 Study

OBJECTIVE To assess whether oral ketamine is safe at higher dosages for sedating children and whether it may be an option for the control of chronic pain in children. STUDY DESIGN A prospective study was performed on 12 children with chronic pain to identify the maximum tolerated dosage of oral ketamine. Participants were given 14 days of oral ketamine, 3 times daily, at dosages ranging from 0.25-1.5 mg/kg/dose. Participants were assessed for toxicity and for pain severity at baseline and on day 14 of treatment. RESULTS Two participants, both treated at 1.5 mg/kg/dose, experienced dose-limiting toxicities (sedation and anorexia). One participant, treated at 1 mg/kg/dose, opted to stop ketamine treatment due to new pain on treatment. Nine participants completed their course of ketamine treatment. Of these 12 children, 5 experienced improvement in their pain scores, 2 with complete resolution of pain, lasting >4 weeks off ketamine treatment. CONCLUSION Oral ketamine at dosages of 0.25-1 mg/kg/dose appears to be safe when given for 14 days to children with chronic pain.

Genomewide association study of atazanavir pharmacokinetics and hyperbilirubinemia in AIDS Clinical Trials Group protocol A5202

Background Atazanavir-associated hyperbilirubinemia can cause premature discontinuation of atazanavir and avoidance of its initial prescription. We used genomewide genotyping and clinical data to characterize determinants of atazanavir pharmacokinetics and hyperbilirubinemia in AIDS Clinical Trials Group protocol A5202. Methods Plasma atazanavir pharmacokinetics and indirect bilirubin concentrations were characterized in HIV-1-infected patients randomized to atazanavir/ritonavir-containing regimens. A subset had genomewide genotype data available. Results Genomewide assay data were available from 542 participants, of whom 475 also had data on estimated atazanavir clearance and relevant covariates available. Peak bilirubin concentration and relevant covariates were available for 443 participants. By multivariate analysis, higher peak on-treatment bilirubin levels were found to be associated with the UGT1A1 rs887829 T allele (P=6.4×10–12), higher baseline hemoglobin levels (P=4.9×10–13), higher baseline bilirubin levels (P=6.7×10–12), and slower plasma atazanavir clearance (P=8.6×10–11). For peak bilirubin levels greater than 3.0 mg/dl, the positive predictive value of a baseline bilirubin level of 0.5 mg/dl or higher with hemoglobin concentrations of 14 g/dl or higher was 0.51, which increased to 0.85 with rs887829 TT homozygosity. For peak bilirubin levels of 3.0 mg/dl or lower, the positive predictive value of a baseline bilirubin level less than 0.5 mg/dl with a hemoglobin concentration less than 14 g/dl was 0.91, which increased to 0.96 with rs887829 CC homozygosity. No polymorphism predicted atazanavir pharmacokinetics at genomewide significance. Conclusion Atazanavir-associated hyperbilirubinemia is best predicted by considering UGT1A1 genotype, baseline bilirubin level, and baseline hemoglobin level in combination. Use of ritonavir as a pharmacokinetic enhancer may have abrogated genetic associations with atazanavir pharmacokinetics.

Outcomes by Sex Following Treatment Initiation With Atazanavir Plus Ritonavir or Efavirenz With Abacavir/Lamivudine or Tenofovir/Emtricitabine

BACKGROUND We aimed to evaluate treatment responses to atazanavir plus ritonavir (ATV/r) or efavirenz (EFV) in initial antiretroviral regimens among women and men, and determine if treatment outcomes differ by sex. METHODS We performed a randomized trial of open-label ATV/r or EFV combined with abacavir/lamivudine (ABC/3TC) or tenofovir/emtricitabine (TDF/FTC) in 1857 human immunodeficiency virus type 1-infected, treatment-naive persons enrolled between September 2005 and November 2007 at 59 sites in the United States and Puerto Rico. Associations of sex with 3 primary study endpoints of time to virologic failure, safety, and tolerability events were analyzed using Cox proportional hazards models. Model-based population pharmacokinetic analysis was performed using nonlinear mixed effects modeling (NONMEM version VII). RESULTS Of 1857 participants, 322 were women. Women assigned to ATV/r had a higher risk of virologic failure with either nucleoside reverse transcriptase inhibitor backbone than women assigned to EFV, or men assigned to ATV/r. The effects of ATV/r and EFV upon safety and tolerability risk did not differ significantly by sex. With ABC/3TC, women had a significantly higher (32%) safety risk compared to men; with TDF/FTC, the safety risk was 20% larger for women compared to men, but not statistically significant. Women had slower ATV clearance and higher predose levels of ATV compared to men. Self-reported adherence did not differ significantly by sex. CONCLUSIONS This is the first randomized clinical trial to identify a significantly earlier time to virologic failure in women randomized to ATV/r compared to women randomized to EFV. This finding has important clinical implications given that boosted protease inhibitors are often favored over EFV in women of childbearing potential. CLINICAL TRIALS REGISTRATION NCT00118898.

Effect of scavenger receptor class B type I antagonist ITX5061 in patients with hepatitis C virus infection undergoing liver transplantation

Hepatitis C virus (HCV) entry inhibitors have been hypothesized to prevent infection of the liver after transplantation. ITX5061 is a scavenger receptor class B type I antagonist that blocks HCV entry and infection in vitro. We assessed the safety and efficacy of ITX5061 to limit HCV infection of the graft. The study included 23 HCV‐infected patients undergoing liver transplantation. The first 13 “control” patients did not receive drug. The subsequent 10 patients received 150 mg of ITX5061 immediately before and after transplant and daily for 1 week thereafter. ITX5061 pharmacokinetics and plasma HCV RNA were quantified. Viral genetic diversity was measured by ultradeep pyrosequencing (UDPS). ITX5061 was well tolerated with measurable plasma concentrations during therapy. Although the median HCV RNA reduction was greater in ITX‐treated patients at all time points in the first week after transplantation, there was no difference in the overall change in the area over the HCV RNA curve in the 7‐day treatment period. However, in genotype (GT) 1–infected patients, treatment was associated with a sustained reduction in HCV RNA levels compared to the control group (area over the HCV RNA curve analysis, P = 0.004). UDPS revealed a complex and evolving pattern of HCV variants infecting the graft during the first week. ITX5061 significantly limited viral evolution where the median divergence between day 0 and day 7 was 3.5% in the control group compared to 0.1% in the treated group. In conclusion, ITX5061 reduces plasma HCV RNA after transplant notably in GT 1–infected patients and slows viral evolution. Following liver transplantation, the likely contribution of extrahepatic reservoirs of HCV necessitates combining entry inhibitors such as ITX5061 with inhibitors of replication in future studies. Liver Transpl 22:287‐297, 2016.

Large-scale identification of clinical and genetic predictors of motor progression in patients with newly diagnosed Parkinson's disease: a longitudinal cohort study and validation

Background Better understanding and prediction of PD progression could improve disease management and clinical trial design. We aimed to use longitudinal clinical, molecular, and genetic data to develop predictive models, compare potential biomarkers, and identify novel predictors for motor progression in PD. We also sought to assess the use of these models in the design of treatment trials in PD. Methods A Bayesian multivariate predictive inference platform was applied to data from the Parkinson’s Progression Markers Initiative (PPMI) study (NCT01141023). We used genetic data and baseline molecular and clinical variables from PD patients and healthy controls to construct an ensemble of models to predict the annualised rate of the Movement Disorder Society-Unified Parkinson’s Disease Rating Scale parts II and III combined. We tested our overall explanatory power, as assessed by the coefficient of determination (R2), and replicated novel findings in an independent clinical cohort of PD patients from the Longitudinal and Biomarker Study in PD (LABS-PD; NCT00605163). The potential utility of these models for clinical trial design was quantified by comparing simulated randomized placebo-controlled trials within the out-of sample LABS-PD cohort. Findings A total of 117 controls and 312 PD cases were available for analysis. Our model ensemble exhibited strong performance in-cohort (5-fold cross-validated R2=41%, 95% CI: 35% – 47%) and significant, though reduced, performance out-of-cohort (R2=9%, 95% CI: 4% – 16%). Individual predictive features identified from PPMI data were confirmed in the LABS-PD cohort of 317 PD patients. These included significant replication of higher baseline motor score, male sex, and increased age, as well as a novel PD-specific epistatic interaction all indicative of faster motor progression. Genetic variation was the most useful predictive marker of motor progression (2.9%, 95%CI: 1.5–4.3%). CSF biomarkers at baseline showed a more modest (0.3%; 95%CI: 0.1–0.5%), but still significant effect on motor progression prediction. The simulations (n=5000) showed that incorporating the predicted rates of motor progression into the final models of treatment effect reduced the variability in the study outcome allowing significant differences to be detected at sample sizes up to 20% smaller than in naïve trials. Interpretation Our model ensemble confirmed established and identified novel predictors of PD motor progression. Improving existing prognostic models through machine learning approaches should benefit trial design and evaluation, as well as clinical disease monitoring and treatment. Funding Michael J. Fox Foundation for Parkinson’s Research and National Institute of Neurological Disorders and Stroke (1P20NS092529-01).