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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 PARTICIPANTSThis 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 MEASURESThe 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.

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The combination of the PCR technique and the synthetic oligonucleotides has proved to be a useful tool in the molecular analysis of HLA class II genes, allowing recognition of as little as a single nucleotide modification in the sequence of the gene. The molecules encoded by these genes have been associated with genetic control of the immune response and with susceptibility to certain diseases. Studies carried out in our laboratory have shown three patterns of humoral immune response in the human volunteers vaccinated with the synthetic protein SPf 66; high, intermediate and low responders. Approximately 73.3% of the low responders were serologically typed as HLA DR4 and 42% as DQw6. These results moved us to look for a subtype (Dw) correlation between the DR4 positive individuals and the different humoral immune response patterns. Using oligo-typing methods after previous amplification of the DR4 B1 exon, we subtyped 20 DR4 volunteers, classified as high, intermediate and low responders. We did not find any direct association between the HLA DR4 Dw special subtype in the high or low responders immunized with the SPf 66 vaccine.

In the first field trial with synthetic malaria vaccine SPf66 in a large population naturally exposed to malaria, 9957 persons greater than 1 year old and residing on the Colombian Pacific coast received three doses of the vaccine. To evaluate vaccine safety, clinical observations were made 30 min and 48 h after each immunization. There were no adverse reactions in 95.7% of cases. In the 4.3% of cases with adverse reactions, local induration and erythema were the most frequent. In a randomly selected group of vaccinees, anti-SPf66 antibody titers were measured after the third dose: 93% of the vaccinees raised antibodies to SPf66. Among these, 55% had titers greater than 1:1600. These results demonstrate the safety and immunogenicity of the SPf66 vaccine in a large field trial.

The synthetic malaria vaccine SPf 66 has been shown to be safe, immunogenic and effective in trials performed with controlled groups naturally and experimentally exposed to the disease. In order to continue the trials in open populations, it was necessary to standardize the vaccination characteristics. We have performed four field trials with soldier volunteers with the aim, among others, of defining the number of doses required, the intervals between applications, the protein concentration, and the adjuvant to be used. In these trials, the vaccinated individuals' immune responses were evaluated by assaying anti-SPf 66 antibody titres, in vitro growth inhibition of the P. falciparum parasite, and the vaccinees' capacity to recognize P. falciparum native proteins. From these results we conclude that the best vaccination schedule, for adults, is three doses administered subcutaneously on days 0, 30 and 180, each containing 2 mg of the synthetic polymerized petide SPf 66 adsorbed to alum hydroxide.

Digital health technologies can provide continuous monitoring and objective, real-world measures of Parkinson’s disease (PD), but have primarily been evaluated in small, single-site studies. In this 12-month, multicenter observational study, we evaluated whether a smartwatch and smartphone application could measure features of early PD. 82 individuals with early, untreated PD and 50 age-matched controls wore research-grade sensors, a smartwatch, and a smartphone while performing standardized assessments in the clinic. At home, participants wore the smartwatch for seven days after each clinic visit and completed motor, speech and cognitive tasks on the smartphone every other week. Features derived from the devices, particularly arm swing, the proportion of time with tremor, and finger tapping, differed significantly between individuals with early PD and age-matched controls and had variable correlation with traditional assessments. Longitudinal assessments will inform the value of these digital measures for use in future clinical trials.