Efficacy of Nilotinib in Patients With Moderately Advanced Parkinson Disease: A Randomized Clinical Trial.

Importance: There is a critical need for careful and independent validation of reported symptomatic efficacy and dopaminergic biomarker changes induced by nilotinib in Parkinson disease (PD). Objectives: To assess safety and tolerability of nilotinib in participants with moderately advanced PD. Secondary and exploratory objectives were to assess its affect on PD disability, pharmacokinetics, cerebrospinal fluid (CSF) penetration, and biomarkers. Design, Setting, and Participants: This was a 6-month, multicenter, randomized parallel-group, double-blind, placebo-controlled trial. Recruitment was from November 20, 2017, to December 28, 2018, and follow-up ended on September 9, 2019. The study was conducted at 25 US sites. The study approached 173 patients, of whom 48 declined, 125 were screened, and 76 who received a stable regimen of PD medications were enrolled (39% screen failure). Interventions: Participants were randomized 1:1:1 to placebo, 150-mg nilotinib, or 300-mg nilotinib once daily orally for 6 months, followed by 2-month off-drug evaluation. Main Outcomes and Measures: The primary outcomes were safety and tolerability. The tolerability end point was defined as the ability to complete the study while receiving the assigned dose. An active arm was considered tolerable if the percentage of participants meeting the tolerability end point for that group was not significantly lower than the percentage observed in the placebo group. Secondary outcomes included change in PD disability (Movement Disorder Society Unified Parkinson's Disease Rating Scale [MDS-UPDRS], Part II OFF/ON). Exploratory outcomes included serum and CSF pharmacokinetic profile, and CSF dopaminergic biomarkers. Results: At baseline, mean (SD) participants' age was 64.6 (7.5) years, 52 were male (68%), mean (SD) disease duration was 9.9 years (4.7), MDS-UPDRS Part 1-3 OFF score was 66.4 (19.3), ON score was 48.4 (16.2), and Montreal Cognitive Assessment score was 27.1 (2.2). The number of participants who completed the study receiving the assigned dose were 21 (84%), 19 (76%), and 20 (77%) in the placebo, 150-mg, and 300-mg arms, respectively. Both active doses had acceptable safety profile. The most common reasons for drug suspension were asymptomatic, dose-dependent elevations of amylase, and/or lipase. Nilotinib, 150 mg and 300 mg, exhibited worse MDS-UPDRS-3 ON scores compared with placebo, achieving significance for nilotinib, 300 mg, at month 1 (P < .01). There was no difference in the change of MDS-UPDRS-3 OFF from baseline to 6 months between groups (P = .17). Cerebrospinal fluid/serum ratio of nilotinib concentration was 0.2% to 0.3%. There was no evidence of treatment-related alteration of dopamine metabolites in the CSF. Conclusions and Relevance: While we demonstrated acceptable safety and tolerability of nilotinib in our cohort, the low CSF exposure and lack of biomarkers effect combined with the efficacy data trending in the negative direction indicate that nilotinib should not be further tested in PD. Trial Registration: ClinicalTrials.gov Identifier: NCT03205488.

Peripheral Biomarkers of Parkinson's Disease Progression and Pioglitazone Effects.

Pioglitazone, an oral hypoglycemic agent, recently failed to show promise as a disease-modifying agent in a 44-week phase 2 placebo-controlled study in 210 Parkinson's disease (PD) subjects. We analyzed peripheral biomarkers, including leukocyte PGC-1α and target gene expression, plasma interleukin 6 (IL-6) as a marker of inflammation, and urine 8-hydroxydeoxyguanosine (8OHdG) as a marker of oxidative DNA damage. Baseline or changes from baseline in biomarker levels were not associated with the rate of progression of PD. Pioglitazone did not significantly alter biomarker levels. Other agents that more effectively target these mechanisms remain of potential interest as disease modifying therapies in PD.

Physical activity as a coping strategy for smoking cessation in mid-life and older adults.

Smoking prevalence for those ages 45-65 is higher than the national average and the number of mid-life and older smokers is expected to increase as baby boomers age. Cessation, even after age 65, confers health benefits. Both physiologic and psychological mechanisms support use of physical activity (PA) as a coping tool for quitting and improving health. This study focused on use of PA for coping with urges to smoke, factors associated with use, and whether use of PA was associated with abstinence at 12 months for 799 smokers ages 50 and older. Only 11.6% used PA for coping, with walking the most common PA. Females were more likely to use PA relative to males. Though in the predicted direction, use of PA was not significantly associated with 12-month abstinence. Male gender and higher baseline self-efficacy to quit were associated with 12 month abstinence. Encouraging use of PA during smoking cessation does not impede quitting and may improve health outcomes. Further research on whether PA increases abstinence with a larger sample of mid-life and older adults is indicated.